JP2023179498A - CRYSTALLINE FORMS OF 3-(IMIDAZO[1,2-b]PYRIDAZIN-3-YLETHYNYL)-4-METHYL-N-{4-[(4-METHYLPIPERAZIN-1-YL)METHYL]-3-(TRIFLUOROMETHYL)PHENYL}BENZAMIDE AND ITS MONOHYDROCHLORIDE SALTS - Google Patents

Abstract

To provide polymorphic forms of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide, which is a multi-targeted tyrosine-kinase inhibitor useful for treatment of chronic myeloid leukemia (CML) and other diseases.SOLUTION: The invention provides Forms A through K of novel crystalline 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide monohydrochloride salts.SELECTED DRAWING: Figure 12

Description

Cross-references to Related Applications This application is filed under U.S. Provisional Patent Application No. 61/736,543, filed on December 12, 2012; and claims priority to U.S. Provisional Patent Application No. 61/788,208, filed March 15, 2013, which is incorporated herein by reference in its entirety.

The present application refers to 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl ) phenyl}benzamide and 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(tri The present invention relates to novel crystalline forms of fluoromethyl)phenyl}benzamide monohydrochloride, compositions containing such crystalline forms, and methods of preparation and use thereof. 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl} Benzamide has the chemical formula C ₂₉ H ₂₇ F ₃ N ₆ O, which corresponds to a formula weight of 532.56 g/mol. Its chemical structure is shown below:

3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl} The CAS registration number for benzamide is 943319-70-8.

3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl} Benzamide monohydrochloride has the chemical formula C ₂₉ H ₂₈ ClF ₃ N ₆ O, which corresponds to a formula weight of 569.02 g/mol. Its chemical structure is shown below:

3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl} The CAS registration number for benzamide monohydrochloride is 1114544-31-8.

3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl} The United States Nonproprietary Name (USAN) and International Nonproprietary Name (INN) of benzamide is ponatinib. Other chemical names for ponatinib include benzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl) methyl]-3-(trifluoromethyl)phenyl] and 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methyl piperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide.

3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl} The United States Nonproprietary Name (USAN) and International Nonproprietary Name (INN) of benzamide monohydrochloride is ponatinib hydrochloride. Other chemical names for ponatinib hydrochloride include benzamide, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1- piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-, hydrochloride (1:1) and 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl -N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide monohydrochloride.

Ponatinib is a multi-targeted tyrosine kinase inhibitor useful in the treatment of diseases including chronic myeloid leukemia (CML). Ponatinib hydrochloride is indicated for the treatment of adult patients with chronic, transitional, or blast crisis CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) who are resistant or intolerant to previous tyrosine kinase inhibitor therapy. It is a small molecule pan-BCR-ABL inhibitor in clinical development for therapeutic use. Other tyrosine kinase inhibitors relevant to the treatment of such CML or Ph+ALL include GLEEVEC® (imatinib mesylate) and TASIGNA® (nilotinib) (both Novartis AG), SPRYCEL® ) (dasatinib) (Bristol Myers Squibb) and BOSULIF® (bosutinib) (Pfizer). A new drug application (NDA) for ponatinib hydrochloride was submitted to the US FDA on July 30, 2012. The US FDA approved this NDA on December 14, 2012, and ponatinib hydrochloride is now commercially available under the trade name ICLUSIG® (ponatinib).

Additionally, ponatinib hydrochloride may be clinically useful in the treatment of other disorders or conditions that involve inhibition of other protein kinases. For a discussion of such kinases and the disorders or pathologies caused by them, see O'Hare, T.; , et al, Cancer Cell, Vol. 16, No. 5, 401-412 (2009) and WO 2011/053938, which are incorporated herein by reference for all purposes.

Understanding the possible polymorphisms of active pharmaceutical ingredients such as ponatinib and ponatinib hydrochloride is useful in drug development. Without knowledge of the specific polymorphisms present or desired in an API, the manufacturing of the API may be inconsistent and, as a result, the results obtained with the drug may vary between different lots of the API. . Furthermore, for much the same reasons as above, it is important to discover as many polymorphs of an API as possible so that the stability of the polymorph can be systematically determined over time. After selecting a specific polymorph for drug development, it becomes important to be able to reproducibly prepare that polymorph. Additionally, it is desirable to have a process for producing APIs such as ponatinib and ponatinib hydrochloride with high purity, as impurities can affect drug performance.

The earliest patent publication known to the applicant that discloses the chemical structure of ponatinib hydrochloride is WO 2007/075869, which also belongs to the applicant (ARIAD Pharmaceuticals), and is incorporated by reference for all purposes. incorporated herein by. Example 16 of WO 2007/075869 states that the product was obtained as a solid with 533 m/z (M+H). This mass corresponds to the free base of ponatinib. Example 16 also describes the preparation of ponatinib monohydrochloride. In Example 16, there is no part that specifically mentions that the obtained ponatinib hydrochloride was crystalline, nor does it specify the specific crystal form of ponatinib hydrochloride.

U.S. Patent Application No. 11/644,849, published as U.S. Patent Application Publication No. 2007/0191376, is a counterpart application of WO 2007/075869, and No. 114,874, which is incorporated herein by reference for all purposes. US Patent Application Publication No. 13/357,745 is a continuation of US Patent Application No. 11/644,849, which is also incorporated herein by reference for all purposes.

Other patent applications of the applicant that deal with ponatinib hydrochloride and have been published as of the filing date of this application include WO 2011/053938 and WO 2012/139027. is incorporated herein by reference for all purposes. Similar to WO 2007/075869, both WO 2011/053938 and WO 2012/139027 do not specify a specific crystalline form of ponatinib hydrochloride.

International Publication No. 2007/075869

It has now been established that both ponatinib and ponatinib hydrochloride can exist in polymorphic forms, including certain crystalline forms, some of which may be suitable for pharmaceutical formulation development.

In one aspect, the present disclosure relates to polymorphs of ponatinib. The polymorphs of ponatinib are designated herein as Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, and Form K.

In another aspect, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a polymorph of ponatinib disclosed herein and at least one pharmaceutically acceptable carrier, excipient or excipient. relating to things.

In yet another aspect, the present disclosure relates to a substantially pure crystalline form of ponatinib hydrochloride. Substantially pure crystalline forms of ponatinib hydrochloride are referred to herein as Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, and Form K. Name it.

In yet another aspect, the present disclosure provides a therapeutically effective amount of a substantially pure crystalline form of ponatinib hydrochloride disclosed herein and at least one pharmaceutically acceptable carrier, excipient or excipient. A pharmaceutical composition comprising:

In yet another aspect, the present disclosure provides a process for preparing a substantially pure crystalline form of ponatinib hydrochloride by contacting ponatinib with hydrochloric acid.

In yet another aspect, the present disclosure relates to a method of treating a disorder or condition in a human that responds to protein kinase inhibition by administering to the human a therapeutically effective amount of a polymorph of ponatinib disclosed herein. . In certain embodiments, the disorder or condition is chronic myeloid leukemia (CML).

In yet another aspect, the present disclosure provides methods for treating human disorders in which inhibition of protein kinases is amenable to protein kinase inhibition by administering to the human a therapeutically effective amount of a substantially pure crystalline form of ponatinib hydrochloride disclosed herein. or relating to methods of treating a medical condition. In certain embodiments, when the protein kinase is Bcr-Abl or a variant thereof, the disorder or condition is chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL).

The following drawings are a part of the present specification and are included to illustrate in detail certain aspects of the invention. A better understanding of the invention may be obtained by reference to one or more of these drawings and the detailed description of specific embodiments presented herein.

A summary of 11 solid state forms of ponatinib hydrochloride, including HCl polymorphs and pseudopolymorphs, discovered and identified as Forms A through K and disclosed herein. 1 is a summary of specific solid state forms of ponatinib hydrochloride discovered and identified in FIG. 1 and disclosed herein. The legend of Figure 2 is as follows: ^a Starting material: HCl1 form or amorphous material (Am) obtained by lyophilization. ^b Occ: Total occurrence rate includes 216 experiments performed in the second stage (described in Example 1 herein) in which 39 samples were further wet analyzed or The mother liquor was evaporated and analyzed, and a total of 254 materials were characterized. For example, "(3, 1.2%)" corresponds to the shape appearing 3 times out of 254 measurements and its percentage being 1.2%. In 62 of 254 measurements (9%), the yield of product was too low to identify the solid form or the material was wet. ^dAm : Amorphous. Figure 3 is a characteristic X-ray powder diffraction (XRPD) pattern of two batches of Form A ponatinib hydrochloride, with data for each batch obtained before and after DVS humidity cycling. The vertical axis shows the relative intensity (expressed in counts), and the horizontal axis shows the angle (2θ). Figure 2 is a characteristic X-ray powder diffraction (XRPD) pattern obtained from Form A of ponatinib hydrochloride. The vertical axis shows the relative intensity (expressed in counts), and the horizontal axis shows the angle (2θ). Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained from Form A ponatinib hydrochloride. The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). Figure 3 is a characteristic thermogravimetric analysis (TGA) and thermogravimetric analysis combined with volatile mass spectrometry (TGMS) scan obtained from Form A ponatinib hydrochloride. Figure 2 is a characteristic ¹ H-NMR spectrum (600 MHz) of ponatinib hydrochloride in solution obtained from Form A ponatinib hydrochloride in DMSO-d ₆ at 300 K. The vertical axis shows normalized intensity, and the horizontal axis shows chemical shift (ppm). Figure 2 is a characteristic ¹⁹ F-NMR spectrum (564 MHz) of ponatinib hydrochloride in solution obtained from Form A ponatinib hydrochloride in DMSO-d ₆ at 300K. The vertical axis shows normalized intensity, and the horizontal axis shows chemical shift (ppm). Figure 2 is a characteristic ¹³ C-NMR spectrum (151 MHz) of ponatinib hydrochloride in solution obtained from Form A ponatinib hydrochloride in DMSO-d ₆ at 300K. The vertical axis shows normalized intensity, and the horizontal axis shows chemical shift (ppm). Characteristic mass spectral patterns obtained from Form A ponatinib hydrochloride, where the upper mass spectral pattern is the observed mass of Form A and the lower mass spectral pattern is the daughter of the parent shown in Form A above. This is the spectrum of ions. The vertical axis shows the relative abundance, and the horizontal axis shows the atomic weight (m/z). Figure 2 is a characteristic mass spectral fragmentation pattern of Form A ponatinib hydrochloride. The vertical axis shows the relative abundance, and the horizontal axis shows the atomic weight (m/z). FIG. 2 illustrates the structure of Form A ponatinib hydrochloride according to the data presented in the table entitled "Crystal Data and Structural Refinement of Form A Ponatinib Hydrochloride" herein. The atoms in FIG. 12 are color-coded according to the type of atom: carbon is gray, nitrogen is blue, oxygen is red, hydrogen is white, fluorine is yellow, and chlorine is green. Figure 2 is a characteristic FT-IR spectrum obtained from Form A of ponatinib hydrochloride. The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ). Figure 2 is a characteristic HPLC spectrum obtained from Form A ponatinib hydrochloride. The vertical axis shows absorbance units (mAU), and the horizontal axis shows time (minutes). FIG. 3 shows a comparison of the characteristic X-ray powder diffraction (XRPD) pattern obtained from Form A ponatinib hydrochloride (bottom) with the XRPD patterns of Forms B (center) and C (top). The vertical axis shows the relative intensity (expressed in counts), and the horizontal axis shows the angle (2θ). Figure 2 is a characteristic HPLC spectrum obtained from Form B ponatinib hydrochloride. The vertical axis shows absorbance units (mAU), and the horizontal axis shows time (minutes). Figure 2 is a comparison of the characteristic X-ray powder diffraction (XRPD) pattern obtained from Form C ponatinib hydrochloride (top) and the XRPD pattern of Form A (bottom). The vertical axis shows the relative intensity (expressed in counts), and the horizontal axis shows the angle (2θ). Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained from Form C ponatinib hydrochloride. The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). Figure 2 is a characteristic thermogravimetric analysis (TGA) scan obtained from Form C ponatinib hydrochloride. Figure 3 is a characteristic TGMS thermogram obtained from Form C ponatinib hydrochloride. Figure 2 is a characteristic HPLC spectrum obtained from Form C ponatinib hydrochloride. The vertical axis shows absorbance units (mAU), and the horizontal axis shows time (minutes). Figure 2 is a comparison of the characteristic X-ray powder diffraction (XRPD) pattern obtained from Form D ponatinib hydrochloride with the XRPD patterns of Form A and certain other crystalline forms within the HCl3 class. The vertical axis shows the relative intensity (expressed in counts), and the horizontal axis shows the angle (2θ). Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained from Form D ponatinib hydrochloride. The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). Figure 2 is a characteristic thermogravimetric analysis (TGA) scan obtained from Form D ponatinib hydrochloride. Figure 2 is a characteristic FT-IR spectrum obtained from Form D ponatinib hydrochloride. The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ). Form A starting material is shown in red, Form D (PSM1) in blue. Figure 2 is a characteristic HPLC spectrum obtained from Form D ponatinib hydrochloride. The vertical axis shows absorbance units (mAU), and the horizontal axis shows time (minutes). Figure 2 is a comparison of the characteristic X-ray powder diffraction (XRPD) pattern obtained from Form F ponatinib hydrochloride with the XRPD patterns of Form A and certain other crystalline forms within the HCl5 class. The vertical axis shows the relative intensity (expressed in counts), and the horizontal axis shows the angle (2θ). FIG. 2 shows two characteristic differential scanning calorimetry (DSC) scans obtained from Form F ponatinib hydrochloride. The upper scan is the DSC curve of VDS1. The bottom scan is the DSC curve of VDS2. The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). Figure 3: Overlay of characteristic thermogravimetric analysis obtained from Form F of ponatinib hydrochloride (VDS1) with SDTA (top) and TGMS (bottom) scans. Overlay of characteristic thermogravimetric analysis (top) and TGMS (bottom) scans obtained from Form F ponatinib hydrochloride (VDS2). 1 is a characteristic FT-IR spectrum obtained from Form F ponatinib hydrochloride. The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ). Form A starting material is shown in red, Form F (VDS1) in green. 1 is a characteristic FT-IR spectrum obtained from Form F ponatinib hydrochloride. The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ). Form A starting material is shown in purple, Form F (VDS2) in red. Figure 2 is a characteristic HPLC spectrum obtained from Form F ponatinib hydrochloride (VDS2). The vertical axis shows absorbance units (mAU), and the horizontal axis shows time (minutes). Figure 2 is a comparison of the characteristic X-ray powder diffraction (XRPD) pattern obtained from Form H ponatinib hydrochloride with the XRPD patterns of Form A (bottom) and certain other crystalline forms within the HCl6 class. The vertical axis shows the relative intensity (expressed in counts), and the horizontal axis shows the angle (2θ). Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained from Form H ponatinib hydrochloride. The upper scan is the DSC curve of VDS3. The bottom scan is the DSC curve of VDS4. The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). Overlay of characteristic thermogravimetric analysis (top) and TGMS (bottom) scans obtained from Form H of ponatinib hydrochloride (VDS3). Overlay of characteristic thermogravimetric analysis (top) and TGMS (bottom) scans obtained from Form H of ponatinib hydrochloride (VDS4). Figure 2 is a characteristic FT-IR spectrum obtained from Form H of ponatinib hydrochloride. The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ). Form A starting material is shown in purple, Form H (VDS3) in red. Figure 2 is a characteristic FT-IR spectrum obtained from Form H of ponatinib hydrochloride. The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ). Form A starting material is shown in purple, Form H (VDS4) in red. Figure 2 is a characteristic HPLC spectrum obtained from Form H of ponatinib hydrochloride (VDS4). The vertical axis shows absorbance units (mAU), and the horizontal axis shows time (minutes). Figure 2 is a superposition of the characteristic X-ray powder diffraction (XRPD) patterns of each solid form identified in Figure 1, with the vertical axis representing relative intensity (number of counts) and the horizontal axis representing 2-theta (angle). The solid forms and solvents in this figure are as follows from bottom to top: starting material ponatinib HCl (HCl1) (form A), HCl2 form (QSA12.1, solvent: water) (form B), HCl2b form. (QSA21.1, solvent: water) (form C), HCl3 class form (GRP12.1, solvent: toluene) (form D), mixture HCl1+HCl4 (GRP1.1, solvent: hexafluorobenzene) (form E), HCl5 form (VDS28.1, solvent: butyl acetate) (form F), HCl5b form (VDS28.2 after drying, solvent: butyl acetate) (form G) and HCl6 class (VDS6.1, solvent: methanol) (form H ). (Top to bottom, left to right): HCl6 class (VDS6.1, vds050.0c:E1), HCl5 type (VDS28.1, vds05.0c:B3), HCl5b type (VDS28.2, vds05. 1c:B6), mixture HCl1+HCl4 (GRP1.1, grp02.0c:A1), HCl3 class form (GRP12.1, grp02.1c:L1), HCl2 form (QSA12.1, qsa00.1c:A2) and HCl2b form (QSA21.1, qsa00.1c:J2) is a diagram showing a representative digital image. Figure 2 is a characteristic X-ray powder diffraction (XRPD) pattern obtained from Form J ponatinib hydrochloride. The vertical axis shows the relative intensity (expressed in counts), and the horizontal axis shows the angle (2θ). Figure 2 is a characteristic X-ray powder diffraction (XRPD) pattern obtained from Form K ponatinib hydrochloride. The vertical axis shows the relative intensity (expressed in counts), and the horizontal axis shows the angle (2θ). Figure 3 shows the characteristic XRPD patterns of Form A ponatinib hydrochloride (lower pattern) and amorphous ponatinib hydrochloride (upper pattern) (solvent: 2,2,2-trifluoroethanol), vertically The axis represents relative intensity (count number), and the horizontal axis represents 2 theta (angle). Amorphous 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl) 1 is a characteristic differential scanning calorimetry (DSC) thermogram of phenyl}benzamide monohydrochloride. A strong endothermic event was observed that peaked at 259.4°C, which corresponds to the melting point of this amorphous form. The vertical axis represents the heat flow [mW], and the horizontal axis represents the temperature (° C.). Figure 2 is a characteristic HPLC spectrum obtained from Form H of ponatinib hydrochloride (VDS4). The vertical axis shows absorbance units (mAU), and the horizontal axis shows time (minutes). The vertical axis shows absorbance units (mAU), and the horizontal axis shows time (minutes). Figure 2 is a table summarizing the solid state forms of ponatinib, including polymorphs and pseudopolymorphs identified as Forms A-J. This is a table summarizing the occurrence rate, crystallization method, physical form, endotherm, and purity of polymorphs and pseudopolymorphs of ponatinib identified as Forms A to J. FIG. 2 shows the molecular structure and numbering scheme of Form A ponatinib free base crystals (anhydride) determined by single crystal X-ray analysis. FIG. 3 shows simulated and experimentally obtained XRPD patterns of Form A ponatinib free base crystals (anhydrous). Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained from Form A crystals of ponatinib free base (anhydrous). The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). FIG. 3 shows the molecular structure and numbering scheme of B clasponatinib/1,4-dioxane (1:1) solvate (Form B) determined by single crystal X-ray analysis. Figure 3 is a simulated XRPD pattern of B clasponatinib/1,4-dioxane (1:1) solvate (Form B). FIG. 3 shows the molecular structure and numbering scheme of B clasponatinib/perfluorobenzene (1:1) solvate (Form B) determined by single crystal X-ray analysis. B Simulated and experimentally obtained XRPD patterns of clasponatinib/perfluorobenzene (1:1) solvate (Form B). Form B ponatinib/2-methylTHF (1:0.4) solvate (top pattern); Form B ponatinib/cyclohexanone (1:1) solvate (middle pattern); and Form A (bottom pattern). ) is a diagram showing an XRPD pattern of. Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained from B class 1:1 ponatinib/cyclohexanone solvate (QSA7.1). The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). Figure 2 is a superposition of characteristic TGA and SDTA thermograms of B class 1:1 ponatinib/cyclohexanone solvate (QSA7.1). B Class 1: Characteristic differential scanning calorimetry (DSC) scan obtained from 0.4 ponatinib/2-methyl THF solvate (GEN8.1). The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). B Class 1: Overlay of characteristic TGA and SDTA thermograms of 0.4 ponatinib/2-methylTHF solvate (GEN8.1). Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained from low crystalline Form C ponatinib (GEN3.1). The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). Figure 2 is an overlay of characteristic TGA and SDTA thermograms of low crystalline Form C ponatinib (GEN3.1). Figure 3 shows the XRPD patterns of low crystalline Form C ponatinib (GEN3.1) (top pattern) and Form A (bottom pattern). Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained from Form D of ponatinib (GEN5.1R1). The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). Figure 2 is an overlay of characteristic TGA and SDTA thermograms of Form D ponatinib (GEN5.1R1). FIG. 3 shows the XRPD patterns of Form D ponatinib (middle pattern) and Form A (bottom pattern). Also shown are the XRPD patterns of clasponatinib solvate B and ponatinib Form D mixture (top pattern). Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained from E-clasponatinib/THF 1:1 solvate (GEN7.1). The vertical axis shows the heat flow rate [mW], and the horizontal axis shows the temperature (°C). FIG. 3 is an overlay of characteristic TGA and SDTA thermograms of E-clasponatinib/THF 1:1 solvate (GEN7.1). XRPD patterns of E-clasponatinib/THF1:1 solvate (GEN7.1) (top pattern); E-clasponatinib/chloroform solvate (SLP3.1) (middle pattern); and Form A (bottom pattern). FIG. Figure 2 is a superposition of characteristic TGA and SDTA thermograms of Form F ponatinib (AS16.2). Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained from Form H (VLD1, dry solid from stock). The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). Overlay of characteristic TGA and SDTA thermograms of Form H (VLD1, dry solid from stock). Figure 2 shows the following series of XRPD patterns: Plot 1 is Form H (VLD2 experiment, 2 weeks and after drying); Plot 2 is Form H (VLD1 experiment, 2 weeks and after drying); Plot 3 is Form H (VLD1 experiment, dry solids from stock after DVS); Plot 4 is Form H (VLD1, dry solids from stock); Plot 5 is Form H (VLD19); bottom The plot is the XRPD of form A. FIG. 3 is a superimposition of the characteristic FT-IR spectrum obtained from Form H ponatinib and the FT-IR spectrum obtained from Form A. The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ). This is a diagram in which the characteristic FT-IR spectrum obtained from Form H ponatinib and the FT-IR spectrum obtained from Form A in the wavelength range of 1750 to 600 nm are superimposed. The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ). Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained from Form I (GEN9.1). The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). Figure 2 is a superposition of characteristic TGA and SDTA thermograms of type I (GEN9.1). FIG. 3 shows an overlapping XRPD pattern of ponatinib Form I (top pattern) and Form A (bottom pattern). Figure 2 shows the superposition of the following XRPD patterns: Plot 6 is the XRPD pattern of Form A (VDS2, after stability testing); Plot 7 is the XRPD pattern of Form J (VDS2); Plot 8 is the XRPD pattern of Form J (VDS2); Plot 9 is another XRPD pattern of Form A ponatinib. FIG. 3 shows a characteristic FT-IR spectrum obtained from Form J superimposed with the FT-IR spectrum obtained from Form A. The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ). FIG. 2 is a diagram showing the characteristic FT-IR spectrum obtained from the J-type and the FT-IR spectrum obtained from the A-type in the wavelength range of 1750 to 600 nm, superimposed. The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ). Selected ponatinib free base polymorphisms (from bottom to top): Form A (SM); Class B (QSAS7.1); Form C, low crystallinity (GEN3.1); Form D (GEN5.1) ; E class (SLP3.1); F type (SLP10.1); G type (AS19.1); H type (VDL19.1); I type, low crystallinity (GEN9.1); and J type, low It is a diagram showing the results of XRPD obtained with crystallinity (VDS10.1) superimposed. Figure 3 shows an overlay of the XRPD patterns of the free base starting material, the two patterns representing two batches (F09-05575: bottom pattern; and F09-05576: top pattern). Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained for batch F09-05575 of ponatinib free base starting material. The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). Figure 2 is a characteristic differential scanning calorimetry (DSC) scan obtained for batch F09-05576 of ponatinib free base starting material. The vertical axis shows the heat flow [mW], and the horizontal axis shows the temperature (°C). Figure 2 is an overlay of characteristic TGA and SDTA thermograms of ponatinib free base starting material batch F09-05575. Figure 2 is an overlay of characteristic TGA and SDTA thermograms of ponatinib free base starting material batch F09-05576. Figure 2 is a table summarizing the physical stability of several solid forms of ponatinib. Figure 2 is a table summarizing the results of scale-up experiments for selected free base forms. Figure 2 is a table summarizing various characterizations of the free base form of ponatinib reproduced on a 120 mg scale.

3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl} Benzamide and 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl) It has now been found that both phenyl}benzamide monohydrochloride can be obtained in various solid crystalline forms.

The terms "crystalline form," "polymorph," or "polymorph" may be used interchangeably herein, and include differences in thermodynamic stability, physical parameters, X-ray structure, DSC and preparation process, etc. Refers to an amorphous form of ponatinib or ponatinib hydrochloride or a crystalline form of ponatinib or ponatinib hydrochloride that differs from other form(s) of ponatinib or ponatinib hydrochloride as determined by certain physical properties.

While polymorphism classically refers to the ability of a compound to crystallize into two or more different crystal species (same chemical structure but completely different physicochemical properties), polymorphism The term ``morphic'' typically applies to crystalline forms of solvates and hydrates. However, for purposes of this disclosure, both true polymorphs and pseudopolymorphs (ie, hydrates and solvates) are included within the terms "crystalline form" and "polymorph." Additionally, "amorphous" refers to irregular solids.

It should be noted that although the major XRPD peaks may be the same for different samples of a particular crystalline form, there may be differences in the XRPD patterns with respect to minor peaks. With respect to XRPD, the term "about" when used with respect to the maximum value of XRPD (expressed in 2-theta degrees) generally means within 0.3 degrees 2-theta of a given value. Alternatively, the term "about" can mean a value that one of skill in the art would consider to be within acceptable standard errors (in any context, including this context). As used herein, the terms "isolated" and "substantially pure" refer to approximately It means that more than 50% of crystalline ponatinib or ponatinib hydrochloride is present in the identified crystalline form (as can be determined by methods of the art).

Definitions and Abbreviations Solvent Abbreviations:
・DCM: dichloromethane ・DMA: N,N-dimethylacetamide ・DMF: N,N-dimethylformamide ・DMSO: dimethyl sulfoxide ・TFE: 2,2,2-trifluoroethanol ・THF: tetrahydrofuran ・2-methylTHF: 2 -Methyltetrahydrofuran/EtOH: Ethanol/MeOH: Methanol Other abbreviations (in alphabetical order):
・Am: Amorphous ・API: Pharmaceutical active ingredient ・AS: Poor solvent ・CI: Counter ion ・DSC: Differential scanning calorimetry ・DVS: Dynamic vapor sorption ・GRP: ID of crushing experiment
・HPLC: High performance liquid chromatography ・HT-XRPD: High throughput powder X-ray diffraction ・HR-XRPD: High resolution powder X-ray diffraction ・LC: Low crystalline substance ・MS: Mass spectrometry ・PSM: Cooling/evaporation crystallization Experiment ID
・SAS: Solubility assessment ・SDTA: Single differential thermal analysis ・S: Solvent ・SM: Starting material ・TGA: Thermogravimetric analysis ・TGMS: Thermogravimetric analysis combined with mass spectrometry ・VDL: Vapor diffusion into liquid Experiment ID
・VDS: ID of vapor diffusion experiment on solids
・XRPD: Powder X-ray diffraction

Analysis method
XRPD patterns were obtained using an Avantium T2 high- throughput XRPD suite. The plate was mounted on a Bruker GADDS diffractometer equipped with a Hi-Star area detector. The XRPD platform was calibrated using silver behenate for long d-spacings and corundum for short d-spacings.

Data collection was performed at room temperature using monochromatic CuK _α radiation in the 2θ region of 1.5° to 41.5°, which is the part of the XRPD pattern where features are most likely to appear. Two types of 2θ ranges with an exposure time of 90 seconds for each frame (1.5°≦2θ≦21.5° for the first frame, 19.5°≦2θ≦41.5° for the second frame) The diffraction pattern of each well was collected. The XRPD patterns were not subjected to background subtraction or curve smoothing. The carrier material used during the XRPD analysis was one that allowed X-rays to pass through, and only a small amount of background was generated.

The melting characteristics were determined from DSC thermograms recorded with a thermal analysis heat flux DSC822e instrument (Mettler-Toledo GmbH, Switzerland). A small piece of indium (m.p. = 156.6°C; ΔHf = 28.45 J/g) was used to calibrate the temperature and enthalpy of the DSC822e. Samples were sealed in 40 μl standard aluminum pans, punctured with small holes, and heated from 25° C. to 300° C. at a heating rate of 10° C./min in DSC. During measurements, the DSC instrument was purged using dry _N2 gas at a flow rate of 50 ml/min.

Mass loss due to solvent or water loss from various crystal samples was measured by TGA/SDTA. The weight of the sample was monitored during heating with a TGA/SDTA851e instrument (Mettler-Toledo GmbH, Switzerland) to obtain a weight vs. temperature curve. TGA/SDTA851e was temperature calibrated using indium and aluminum. A sample was weighed into a 100 μl aluminum crucible and sealed. A small hole was made in the sealed bag and the crucible was heated from 25°C to 300°C in TGA at a heating rate of 10°C/min. Dry _N2 gas was used for purging.

The gas released from the TGA samples was analyzed with a mass spectrometer Omnistar GSD 301 T2 (Pfeiffer Vacuum GmbH, Germany). The latter is a quadrupole mass spectrometer that analyzes masses in the 0-200 amu range.

Digital Imaging Digital images of all wells of each well plate were automatically collected using a Philips PCVC 840K CCD camera controlled by Avantium Photoslider software.

Atlas Power Press T25 (Specac) was used for the press compression test. The Atlas Power T25 is an electric hydraulic press that operates up to 25 tons.

HPLC Analysis Method HPLC analysis was performed using an Agilent 1200SL HPLC system equipped with UV and MS detectors according to the conditions listed below:

Compound integrity is expressed as a peak area percentage calculated from the area of each peak other than the "injection peak" in the chromatogram and the total peak area as follows:
Peak area % = (peak area / total area) * 100%

The peak area percentage of the compound of interest is used as an indicator of the purity of the components in the sample.

I. Polymorphic forms of ponatinib monohydrochloride A total of 11 polymorphic forms of ponatinib hydrochloride were discovered through XRPD analysis. These 11 novel polymorphs are herein referred to as HCl1 (also referred to herein as "Form A"), HCl2 (also referred to herein as "Form B"), and HCl2b (also referred to herein as "Form B"). HCl3 class (also referred to herein as "Form D"), HCl1+HCl4 mixture (also referred to herein as "Form E"), HCl5 class or simply HCl5 (also referred to herein as "Form F"), ), HCl5b or HCl5 desolvates (also referred to herein as "G form"), HCl6 class (also referred to herein as "H form"), HCl6 desolvates (also referred to herein as "H form"), (also referred to as "Form I"), HCl7 (also referred to herein as "Form J") and HCl8 (also referred to herein as "Form K"). The properties or origins of these 11 types of polymorphs are shown in FIG. Further specific characteristics of the referenced polymorphs are shown in FIG. For example, Form A has been shown to be the anhydrous form of ponatinib hydrochloride, as well as being obtained as a single crystal.

In general, the crystalline form of ponatinib hydrochloride has physical properties (such as increased stability) that are advantageous for solid dosage form commercial formulations compared to the amorphous form of ponatinib hydrochloride. The difference between crystalline ponatinib hydrochloride and amorphous ponatinib hydrochloride is based on the same types of physicochemical data (e.g., DSC, This can be easily seen from XRPD, thermal analysis).

Next, referring to the above methodology, the discovered 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazine-1- yl)methyl]-3-(trifluoromethyl)phenyl}benzamide monohydrochloride.

Characteristics of type A (HCl1):
Anhydrous HCl1 (same crystalline form as the starting material) was the predominant crystalline form found. The chemical structure of ponatinib hydrochloride was determined by nuclear magnetic resonance spectroscopy (NMR), mass spectrometry (MS) and single crystal X-ray crystallography, elemental and chloride analysis, Fourier transform infrared (FT-IR) spectroscopy and This has been clearly confirmed in combination with confirmatory data obtained from ultraviolet (UV) spectroscopy. A preferred solid form of ponatinib hydrochloride is the anhydrous crystalline HCl-1 solid form, ie, Form A.

With respect to FIG. 3, samples of ponatinib HCl, ASI batch 110020 and CGAM batch F08-06057, were analyzed by X-ray powder diffraction (XRPD). In each case, the material was analyzed before and after DVS humidity cycling. XRPD patterns were obtained using a high-throughput XRPD diffractometer. Data collection was performed at room temperature using monochromatic CuK _α radiation in the 2θ region of 1.5° to 41.5°, which is the part of the XRPD pattern where features are most likely to appear. Two types of 2θ ranges with an exposure time of 90 seconds for each frame (1.5°≦2θ≦21.5° for the first frame, 19.5°≦2θ≦41.5° for the second frame) The diffraction pattern of each well was collected. The XRPD patterns were not subjected to background subtraction or curve smoothing. Figure 3 shows the powder X-ray diffraction patterns of each of these materials in the HCl-1 solid form. This powder pattern is consistent with the powder pattern simulated in single crystal X-ray diffraction experiments of the HCl-1 form. The XRPD data obtained before and after the DVS humidity cycling experiment shows that the solid form of HCl-1 is maintained even after humidity cycling. The XRPD pattern of Form A shown in FIG. 3 has the following peaks at angles 2 theta (2θ): 5.9; 7.1; 10.0; 12.5; 16.4; 19.3; 21. 8; 23.8; and 26.1. In certain embodiments, the XRPD pattern of Form A exhibits two peaks, three peaks, four peaks, or five peaks. The term "about" applies to each peak listed for this form and all other forms mentioned in this disclosure.

FIG. 4 shows a characteristic X-ray powder diffraction (XRPD) pattern of Form A of ponatinib hydrochloride, which appears more detailed than XRPD. The XRPD pattern of Form A shown in FIG. 4 has the following 2-theta (2θ) peaks: 5.9; 7.1; 10.0; 12.5; 13.6; 14.1; 15. 0; 16.4; 17.7; 18.6; 19.3; 20.4; 21.8; 22.3; 23.8; 24.9; 26.1; 27.0; 28.4; 30.3; 31.7; and 35.1. In certain embodiments, Form A is characterized by an XRPD pattern that includes one or more of the following two-theta (2θ) peaks: 12.5; 19.3; 23.8; and 26.1. shall be. In certain embodiments, the XRPD pattern of Form A exhibits two peaks, three peaks, four peaks, or five peaks.

Differential vapor sorption (DVS) experiments with HCl-1 were carried out at a constant temperature of 25 °C and a holding time of 60 min per step, with relative humidity ranging from 45% to 95% (sorption) to 0% (desorption). It was then circulated to return to 45% (sorption). The results of this DVS experiment performed with ponatinib HCl CGAM batch F08-060507 showed a water uptake of 1.1% at 95% humidity, and ponatinib HCl ASI batch 110020 showed a water uptake of 1.4% at 95% relative humidity. showed that. This water uptake rate was reversible even when circulated to lower humidity. These results indicate that HCl-1 is not a hygroscopic compound. In addition, the influence of humidity cycling on HCl-1 was evaluated by X-ray powder diffraction (XRPD) analysis before and after the DVS experiment. The XRPD data revealed that humidity cycling had no effect on the solid form of this material and that the material remained in the HCl-1 solid form.

With respect to FIG. 5, the melting point of ponatinib HCl in HCl-1 solid form was determined by differential scanning calorimetry (DSC). A sample of ponatinib HCl, ASI batch 110020, was analyzed in a small hole crucible with a dry _N2 gas purge at a heating rate of 10°C/min and a temperature range of 25°C to 300°C. A strong endothermic event was observed that peaked at 264.1°C, which corresponds to the melting point of Form A.

With respect to FIG. 6, thermogravimetric analysis (TGA) and thermogravimetric analysis combined with mass spectrometry of volatiles (TGMS) were performed on ponatinib HCl, ASI batch 110020. Samples placed in crucibles with small holes were heated from 25°C to 300°C in a TGA instrument at a heating rate of 10°C/min using dry _N2 gas for purging. The gas released from the TGA was analyzed using a quadrupole mass spectrometer. HCl-1 solid form of ponatinib HCl, ASI batch 110020, contained 0.31% water and 0.85% ethanol by weight upon release. In TGA/TGMS experiments, a mass loss of 0.2% (water) and 0.6% (ethanol originating from the crystallization solvent) can be observed in the temperature ranges of 25-130 °C and 130-240 °C, respectively. Shown. This mass loss is consistent with the water and ethanol content at the time of release. Although ethanol is released from the material at higher temperatures than water, this is not due to the HCl-1 solid form of ponatinib HCl as a solvate.

Using a combination of 1D and 2D multiple NMR methods, a thorough liquid-phase NMR study of ponatinib HCl in form A was carried out and ^{the 1} H, ¹⁹ F and ¹³ C resonances were fully assigned, thereby allowing ponatinib HCl to be fully assigned. The chemical structure of was confirmed. Analysis of a sample of ponatinib HCl (ASI batch 110020) in deuterated DMSO (DMSO-d ₆ ) solvent was performed at ARIAD Pharmaceuticals (Cambridge, Mass.). NMR spectra were acquired at a temperature of 300 K on a Bruker Avance III-600 MHz NMR spectrometer equipped with a 5 mm BBFO z-gradient probe. The total ¹ H chemical shift was referenced to the DMSO peak at 2.5 ppm. FIG. 7 shows the 1D ¹ H-NMR spectrum of Form A ponatinib HCl in DMSO- _d6 . ¹ H resonance 32a arises from the protonated piperazine moiety of ponatinib HCl. The EtOH resonances seen in both the ¹ H spectrum (Figure 7) and the ¹³ C spectrum (Figure 9) result from the remaining EtOH present in ponatinib HCl. Figure 8 shows the 1D ¹⁹ F-NMR spectrum of Form A ponatinib HCl in DMSO-d ₆ with a characteristic chemical shift at 57.94 ppm. Figure 9 shows the 1D ¹³ C-NMR spectrum of Form A ponatinib HCl in DMSO- _d6 .

Key chemical shift data for Form A ponatinib monohydrochloride obtained from ^1Η and ^13C -NMR experiments are summarized in Table 1. The number and integrals of signals confirm the number of protons and carbons in the structure of Form A ponatinib HCl. These chemical shift data are reported according to the atomic numbering scheme shown immediately below.

With respect to FIG. 10, mass spectrometry experiments and collisionally activated MS2 fragmentation of Form A ponatinib HCl were performed using a Thermo Finnegan Exactive accurate mass spectrometer and an LTQ XL ion trap mass spectrometer operating in positive ion electrospray mode, respectively. A sample of Form A ponatinib HCl (ASI batch 110020) dissolved in acetonitrile was introduced into the mass spectrometer by injection with a syringe pump. Accurate mass of ponatinib HCl was obtained using an Exactive mass spectrometer in full scan mode. The mass observed in this injection experiment was m/z 533.2269 (MH+), the calculated exact mass was 533.2271 (MH+), and the mass difference was 0.2 mmu (Δppm was -0.38) (Figure 10 , top row). The fragmentation spectrum of ponatinib HCl from an Exactive mass spectrometer is shown in Figure 10, including the product ion from m/z 533.2269 (molecular ion of ponatinib HCl) and all other co-eluted compounds. Contains ions.

Figure 11 shows MS fragmentation data obtained with an LTQ XL ion trap mass spectrometer. FIG. 11(A) shows full scan MS of m/z 533 (MH ⁺ ) of the sample at the time of injection. FIG. 11(B) (MS ² scan) shows the fragment spectrum of the selected mass m/z 533. Figures 11(C) and 11(D) show generated ions derived from m/z 433 and 260, respectively, and the ions m/z 433 and 260 themselves are the first generated ions (molecular ions) derived from m/z 533. be.

The crystal structure of Form A ponatinib hydrochloride was determined using single crystal X-ray diffraction analysis. Ponatinib HCl CGAM batch F08-06057 was used for vapor diffusion crystallization into a liquid to obtain a single crystal of ponatinib HCl in anhydrous HCl-1 form. A single crystal obtained using methanol as a solvent together with ethyl acetate as a poor solvent was analyzed by single crystal X-ray diffraction. Previous experiments have shown that crystals of this form diffract well, leading to the elucidation of the structure of ponatinib HCl shown in FIG. 12, and its crystallographic parameters are summarized in Table 2. The terminal nitrogen of piperazine is the protonation site of ponatinib HCl, consistent with the previously described NMR analysis of ponatinib HCl. Within the crystal structure, a chloride counterion is present immediately adjacent to the protonation site. Based on this structural analysis, it was determined that Form A is anhydrous.

The attenuated total reflectance (ATR) FT-IR spectrum of Form A ponatinib HCl, ASI batch 110020 is shown in FIG. The IR band assignments of selected ponatinib HCl based on FT-IR shown in FIG. 13 are summarized in Table 3.

In FT-IR, the functional group region is seen over a range of 4000 to 1300 cm-1. The region from 3300 to 2800 cm-1 (region A) contains stretching vibrations between hydrogen atoms and some other atoms, probably amide N-H stretching vibrations, aromatic C-H stretching vibrations (imidazo-pyridazine complex Multiple overlapping absorption bands were observed, likely arising from ring and phenyl groups) and aliphatic C–H stretching vibrations (in methyl and methylene groups), all of which are present within the structure of ponatinib HCl. be. The weak band seen at 2100 to 2260 cm-1 (region B) is due to stretching vibration of the triple CC bond. A moderately strong band due to the amide C=O stretching vibration (amide 1) is expected in the range of 1640 to 1690 cm, and this band is observed at 1669.8 cm (region C). I think that the. In the range from 1500 to 1560 cm-1 where two strong bands are observed, there is an absorption band (amide 2) due to secondary amide N--H bending vibration (region D). Weak to moderate bands observed in the range 1300-1600 cm-1 are resonance-stabilized double C-C and double C-N bonds (ring stretching vibrations) of (hetero)aromatics and C- This is due to H bending vibration (derived from methyl and methylene groups) (region E). In particular, the bands of aromatic and aliphatic amine C-N stretching vibrations are observed in the 1250-1335 cm-1 and 1250-1020 cm-1 ranges, where multiple bands are observed, including a strong band at 1314.9 cm-1, respectively. is expected (areas F and G). The fingerprint region from 1300 to 910 cm-1 is combined with a strong and broad band at 1122.6 cm-1 (region H), which may be due to CF stretching vibration. The absorption band in the aromatic region from 910 to 650 cm-1 is mainly due to the out-of-plane bending vibration of the heteroaromatic ring C--H bond, indicating the heteroaromatic nature of the compound (region I). The FT-IR spectral data presented here support the proposed structure of Form A ponatinib hydrochloride.

Experiments were conducted to determine the purity of Form A. With respect to Figure 14, the purity of Form A ponatinib hydrochloride was found to be 99.8160% (area percent).

Characteristics of type B (HCl2):
The solubility evaluation in TFE/water yielded the HCl2 form, which was confirmed by re-measuring the specific sample by XRPD, converting to the HCl2b form after 1 day of storage of the measurement plate under ambient conditions. HCl2 was additionally obtained from an aqueous solvent system (water and MeOH/water) in the experiments performed in the second step described herein and was also converted to the HCl2b form during storage under ambient conditions (Fig. 2 Please refer to the overview).

Form B was analyzed by X-ray powder diffraction (XRPD). Figure 15 shows (from bottom to top): Starting material (Form A), Form HCl2 (Form B) (QSA12.1, solvent: water) and Form HCl2b (Form C) (QSA12.2, under ambient conditions). (remeasured several days later) is shown. In the XRPD pattern shown in FIG. 15, shape B has the following 2-theta (2θ) peaks: 3.1; 6.5; 12.4; 13.8; 15.4; 16.2; 17. 4; 18.0; 20.4; 23.2; 24.4; 26.1; and 26.9. For reference, the XRPD pattern shown in FIG. 15 has the following 2-theta (2θ) peaks in the C shape: 6.5; 12.4; 13.8; 17.4; 18.0; 20. 6; 22.0; 23.0; 25.5; 26.5; and 27.4. In certain embodiments, Form B has one of the following peak 2 theta (2θ): 13.8; 15.4; 17.4; 18.0; 26.1; and 26.9. or a plurality of XRPD patterns. In such embodiments, the XRPD patterns of Forms B and C exhibit two peaks, three peaks, four peaks, or five peaks.

Experiments were conducted to determine the purity of Form B. With respect to Figure 15, the purity of Form B ponatinib hydrochloride was found to be 99.7535% (area percent).

Characteristics of type C (HCl2b):
Form C is the hydrated form. Form HCl2b was initially obtained by conversion of Form B from a multi-day solubility evaluation experiment under ambient conditions or directly from a TFE/water solvent mixture. Form C was also obtained from an aqueous solvent system (water and water/DMSO) in a second stage experiment (see overview in Figure 2).

Form C was analyzed by X-ray powder diffraction (XRPD). Figure 17 shows (from bottom to top): XRPD patterns of starting material (HCl1) and HCl2b form (QSA21.1, solvent: water). In the XRPD pattern shown in FIG. 17, the C-shaped peaks have the following angles of 2-theta (2θ): 3.1; 6.5; 12.4; 13.8; 17.4; 18.0; 20. 6; 22.0; 23.0; 25.5; 26.5; 27.4; 28.4; and 29.0. In certain embodiments, Form C is characterized by an XRPD pattern comprising one or more of the following peaks 2 theta (2θ): 13.8; 17.4; 18.0; and 25.5. shall be. In certain embodiments, the XRPD pattern of Form C exhibits two peaks, three peaks, four peaks, or five peaks.

With respect to FIG. 18, the melting point of Form C ponatinib HCl was determined by differential scanning calorimetry (DSC). Samples were analyzed in small-hole crucibles with a dry N ₂ gas purge at a heating rate of 10° C./min and a temperature range of 25° C. to 300° C. Strong endothermic events were observed at T _peak =122.9°C, T _peak =158.2°C and T _peak =256.2°C.

Figure 19 shows the TGA and SDTGA thermograms of QSA21.1. Figure 20 shows the TGMS thermogram of type C for experiment QSA21.1. A mass loss (water) of 4.3% is observed in the temperature range from 40°C to 140°C. The API:water ratio was estimated to be 1:1.4.

Experiments were conducted to determine the purity of Form C. With respect to Figure 21, the purity of Form C ponatinib hydrochloride was found to be 99.7850% (area percent).

Characteristics of type D (HCl3 class):
The HCl3 class is mostly derived from aromatic solvents, except for the MeOH/acetonitrile mixture, as shown in the overview in Figure 2. Form D was well reproduced on the 120 mg scale using a cooling-steam crystallization method in toluene.

Based on thermal analysis, a representative sample of Form D was named toluene solvated form (AP:toluene 1:0.5). This form desolvated and recrystallized at 199.5°C, and a second melting was observed at 257.6°C (approximately corresponding to the melting point of Form A). The HCl3 class is somewhat hygroscopic, with a water mass uptake of 2.5% at 95% RH. This process was reversible in terms of physical stability and sample appearance.

The HCl3 class samples were found to be physically stable after 8 months of storage under ambient conditions and after DVS cycling. However, in a humidity chamber (40° C./75% RH), the HCl3 class sample converted to HCl1 after one week.

Form D was analyzed by X-ray powder diffraction (XRPD). Figure 22 shows (from bottom to top): HCl1 (AP24534 HCl salt starting material), HCl3 class (PSM17, solvent: toluene), HCl3 (PSM1, solvent: toluene), HCl1+HCl3 (1 at 40°C/75% RH). The XRPD patterns of PSM1) after 1 week and HCl3 (PSM1 after DVS) are shown. In the XRPD pattern shown in Figure 22, HCl3 has the following 2-theta (2θ) peaks: 8.2; 10.1; 10.9; 14.9; 16.0; 16.3; 16.8 17.7; 18.7; 20.2; 22.9; 24.0; 25.6; 26.7; and 28.5. In certain embodiments, Form D is characterized by an XRPD pattern comprising one or more of the following peaks 2 theta (2θ): 8.2; 10.1; 14.9; and 25.6. shall be. In the XRPD pattern shown in Figure 22, HCl3+HCl1 has the following peaks at angles 2 theta (2θ): 6.5; 7.4; 12.5; 13.6; 14.1; 16.7; 17.4 18.0; 19.3; 20.4; 21.8; 24.0; 25.1; 26.3; and 28.0. In certain embodiments, HCl3+HCl1 is characterized by an XRPD pattern that includes one or more of the following peaks 2 theta (2θ): 12.5; 19.3; and 26.3. In certain embodiments, the XRPD pattern of Form D exhibits two peaks, three peaks, four peaks, or five peaks.

With respect to FIG. 23, the melting point of Form D ponatinib HCl (PSM1) was determined by differential scanning calorimetry (DSC). Samples were analyzed in small-hole crucibles with a dry N ₂ gas purge at a heating rate of 10° C./min and a temperature range of 25° C. to 300° C. Strong endothermic events were observed at T _peak =199.5°C, T _peak =204.1°C and T _peak =257.6°C.

Referring to FIG. 24, the TGA and SDTGA thermograms of type D (PSM1) are shown. A mass loss of 7.7% was observed in the temperature range of 120°C to 220°C (toluene, API:solvent ratio 1:0.51).

Referring to FIG. 25, the FT-IR spectra in the 1750-500 cm ⁻¹ region are shown. These data support the proposed structure of Form D ponatinib hydrochloride. Furthermore, this spectrum shows characteristics unique to form D compared to form A.

Experiments were conducted to determine the purity of Form D (PSM1). With respect to Figure 26, the purity of Form D ponatinib hydrochloride was found to be 97.3664% (area percent).

Characteristics of type E (mixture of HCl4 + HCl1):
HCl4 was obtained only as a mixture with form A from the trituration experiments with hexafluorobenzene (see overview in Figure 2).

Form E of ponatinib hydrochloride was found not to be physically stable upon storage under ambient conditions. After 8 months of storage, the mixture HCl1+HCl4 was remeasured by XRPD and found to have converted to form A.

Features of F type (HCl5 class):
Form HCl5 was obtained from vapor diffusion experiments on solids in butyl acetate described herein (see overview in Figure 2). The HCl5 class was characterized by DSC, circulation DSC, TGMS, FTIR, HPLC and DVS. Physical stability under short-term storage conditions (ie, 40° C., 75% RH for 1 week) was investigated. The HCl5 class samples were physically stable as assessed by XRPD after 8 months of storage under ambient conditions. After one week in the humidity chamber (40° C./75% RH), the material was still in the HCl5 class, but a slight difference in the XRPD pattern was seen.

In DVS experiments, the HCl5 class was found to be highly hygroscopic, with a water mass adsorption rate of 37%. The material lost crystallinity as seen by XRPD after the DVS experiment.

Form F was successfully scaled up to the 120 mg scale using the same conditions as the initial experiments identifying the previously discovered polymorphism. Two scale-up experiments were carried out, and the corresponding XRPD patterns showed that it was in a form isomorphic to HCl5. These isomorphic forms, along with HCl5 and HCl5b, were designated the HCl5 class, or form F.

Figure 27 shows (from bottom to top): HCl1 (form A starting material); HCl5 and HCl5b (wet and dry VDS28, solvent: butyl acetate); HCl5 class (VDS1, solvent: butyl acetate), low crystallinity. (VDS1 after DVS); HCl5 class (VDS2, solvent: butyl acetate); and HCl5 class (VDS2 after 1 week at 40°, 75% RH) XRPD patterns are shown. In the XRPD pattern shown in Figure 27, HCl5 has the following 2-theta (2θ) peaks: 6.8; 9.8; 12.4; 16.2; 17.9; 19.0; 24.0 ; and 25.1 are shown. In certain embodiments, HCl5 is characterized by an XRPD pattern that includes one or more of the following peaks 2 theta (2θ): 9.8; 12.4; and 25.1. In the XRPD pattern shown in Figure 27, the HCl5 class (top pattern) has the following 2-theta (2θ) peaks: 7.9; 8.7; 9.7; 11.4; 15.6 ; 16.5; and 25.8 are shown. In certain embodiments, the HCl5 class is characterized by an XRPD pattern that includes one or more of the following peaks 2 theta (2θ): 15.6; 16.5; 25.8. In certain embodiments, the XRPD pattern of Form F exhibits two peaks, three peaks, four peaks, or five peaks.

Referring to FIG. 28, the melting point of Form F ponatinib HCl (PSM1) was determined by differential scanning calorimetry (DSC). Samples from two different experiments were analyzed in small-hole crucibles with a dry _N2 gas purge at a heating rate of 10°C/min and a temperature range of 25°C to 300°C. Samples from one experiment (VDS1, top curve) revealed strong endothermic events occurring at T _peak =120.7°C, T _peak =184.3°C, and T _peak =209.4°C. Samples from the other experiment (VDS2, bottom curve) revealed strong endothermic events at T _peak = 122.1°C, T _peak = 209.7°C, and T _peak = 252.1°C. .

Cyclic DSC experiments showed that when the HCl5 class is desolvated, it converts to a form that melts at about 210° C. and is named "HCl5 desolvate."

Referring to FIG. 29, the TGA/SDTA (VDS1, top) and TGMS (bottom) thermograms of type F are shown. A mass loss of 17.1% (butyl acetate, API:solvent ratio 1:1.01) was observed in the temperature range from 25°C to 160°C. TG-MS analysis showed that the HCl5 class is a butyl acetate solvate with an API:butyl acetate ratio of 1:1 and desolvates at about 120°C. FIG. 30 shows the corresponding TGA/SDTA (top row) and TGMS (bottom row) thermograms of the F-type of VDS2. A mass loss of 16.6% (butyl acetate, API:solvent ratio 1:0.98) was observed in the temperature range from 25°C to 160°C.

31 and 32, FT-IR spectra in the 1750-500 cm ⁻¹ region are shown. These data support the proposed structure of Form F ponatinib hydrochloride. Furthermore, this spectrum shows characteristics specific to the F form compared to the A form.

Experiments were conducted to determine the purity of Form F (VDS2). With respect to Figure 33, the purity of Form D ponatinib hydrochloride was found to be 98.2833% (area percent).

Characteristics of type G (HCl5b):
Form G ponatinib hydrochloride was obtained by conversion of HCl5 by drying under full vacuum for 3 days. HCl form 5b was found to be physically stable even after storage for 8 months under ambient conditions.

Characterization data for Form G are described herein in connection with Form F.

Characteristics of H type (HCl6 class):
HCl6 was obtained from two experiments, evaporation into solution and onto solid in MeOH/water and MeOH solvent systems, respectively (see overview in Figure 2). Due to differences in the time points at which the materials were sampled, the corresponding XRPD patterns were found to be slightly different, indicating, without being bound by theory, that the HCl6 is probably in the isomorphic class form. It shows that there is. The HCl6 class was successfully scaled up to 120 mg using the same conditions as the MeOH evaporation onto solids experiment of the original screening experiment.

The HCl6 class was characterized by DSC, circulation DSC, TGMS, FTIR, HPLC and DVS. Physical stability under short-term storage conditions (ie, 40° C., 75% RH for 1 week) was investigated. Samples of Form H were physically stable as evaluated by XRPD after storage for 8 months under ambient conditions. After one week in the humidity chamber (40° C./75% RH), the material was still in the HCl6 class, but a slight difference in the XRPD was seen.

Figure 34 shows (from bottom to top): Form A (ponatinib hydrochloride starting material), HCl6 class (VDS6, solvent: methanol), HCl6 class (VDS3, solvent: methanol), HCl6 (VDS3 after DVS) , HCl6 class (VDS3 after climate chamber), HCl6 class (VDS4, solvent: methanol) and HCl6 class (VDS4 after DVS) are shown. In the XRPD pattern shown in Figure 34, HCl6 (just above the A-shaped pattern) has the following peaks at angles 2 theta (2θ): 5.9; 8.1; 9.5; 10.7; 13.4 ; 16.0; 17.0; 22.0; 22.8; 24.7; and 28.3. In certain embodiments, HCl6 has an XRPD peak 2 theta (2θ) comprising one or more of the following: 8.1; 10.7; 13.4; 24.7; and 28.3. Features a pattern. In the XRPD pattern shown in Figure 34, the HCl6 class (top pattern) has the following 2-theta (2θ) peaks: 8.0; 10.2; 10.9; 11.8; 14.1 15.4; 16.3; 19.9; 22.3; 23.7; 25.0; and 28.2. In certain embodiments, the HCl6 class is characterized by an XRPD pattern comprising one or more of the following peaks 2 theta (2θ): 10.2; 15.4; 23.7; 25.0. do. In certain embodiments, the XRPD pattern of Form F exhibits two peaks, three peaks, four peaks, or five peaks. In the XRPD analysis of both samples, it was found that almost the same pattern was observed after DVS, but in the TGMS analysis of VDS4, methanol molecules were no longer present in the sample and it was found to be a semi-hydrated form belonging to the HCl6 class. It was found that water molecules forming what appeared to be replaced by water molecules.

With respect to FIG. 35, the melting point of Form H ponatinib HCl was determined by differential scanning calorimetry (DSC). Samples from two different experiments were analyzed in small-hole crucibles with a dry _N2 gas purge at a heating rate of 10°C/min and a temperature range of 25°C to 300°C. The sample from one experiment (VDS3, top curve) revealed a strong endothermic event at T _peak =219.4°C. The other experiment (VDS4, bottom curve) revealed strong endothermic events at T _peak =219.4°C and T _peak =256.8°C.

Referring to FIG. 36, the H-shaped TGA/SDTA (VDS3, top) and TGMS (VDS3, bottom) thermograms are shown. A mass loss of 5.4% (methanol, API:solvent ratio is 1:1.01) was observed in the temperature range from 30°C to 150°C, and a mass loss of 0.3% in the temperature range from 190°C to 220°C. A decrease (methanol, API:solvent ratio of 1:0.05) was observed. For VDS4, the corresponding H-shaped TGA/SDTA (top) and TGMS (bottom) thermograms are shown in FIG. A mass loss of 3.3% (methanol, API:solvent ratio 1:0.6) was observed in the temperature range from 30°C to 150°C, and a mass loss of 0.7% in the temperature range from 190°C to 220°C. A decrease (methanol, API:solvent ratio of 1:0.12) was observed.

38 and 39, FT-IR spectra in the 1750-500 cm ⁻¹ region are shown. These data support the proposed structure of Form H ponatinib hydrochloride. Furthermore, this spectrum shows characteristics unique to Form H compared to Form A.

Experiments were conducted to determine the purity of Form H (VDS4). With respect to Figure 40, the purity of Form H ponatinib hydrochloride was found to be 97.9794% (area percent).

Characteristics of Form I (HCl6 desolvate):
Cyclic DSC experiments performed in conjunction with Form H experiments showed that upon desolvation of the HCl6 class, it converted to a form named "HCl6-desolvate" which melts at about 220°C.

Characteristics of J type (HCl7):
Form J is the pentahydrate of ponatinib HCl and was discovered in connection with single crystal analysis. Form J is the most stable hydrated structure identified, as demonstrated by the competitive slurry in water between the trihydrate and pentahydrate.

Vapor diffusion experiments performed in the solvent mixture methanol/water (20:80) with n-butyl acetate as the antisolvent yielded single crystals of suitable size. One parallelepiped single crystal with dimensions of approximately 0.45 x 0.25 x 0.12 was collected from the crystallization vial and placed on a glass fiber. The crystallographic data (collected up to θ=27.5°) are listed in Table 4.

The asymmetric unit contains a cation, a chloride anion and five water molecules (pentahydrate). Water molecules are bonded to anions, cations, and adjacent water molecules via hydrogen bonds (H bonds).

An important consequence of the parent H-bond configuration is that in this crystal both charged atoms (i.e., the protonated nitrogen and chloride anion of API) are bridged/separated by multiple water molecules.

Figure 43 shows the characteristic X-ray powder diffraction (XRPD) pattern of Form J ponatinib hydrochloride. The J-shaped XRPD pattern shown in FIG. 43 has two-theta (2θ) peaks with relative intensities of 20% or more: 6.1; 7.0; 13.3; 16.4; 20.7; 22. 2; 23.9; 25.5; and 29.1. In certain embodiments, Form J is characterized by an XRPD pattern that includes one or more of the following peaks 2 theta (2θ): 7.0; 22.2; and 25.5. In certain embodiments, the J-shaped XRPD pattern exhibits two peaks, three peaks, four peaks, or five peaks.

Characteristics of type K (HCl8):
Form K was discovered in connection with single crystal analysis. Single crystals were grown in mild evaporation experiments performed with a 50:50 TFE/H2O mixture. A massive single crystal with a size of approximately 0.40 x 0.30 x 0.25 mm was analyzed. Although the crystals were large, there was very little diffraction, indicating that there were irregularities in the structure. Therefore, measurements were recorded only up to θ=25°. Crystallographic parameters are listed in Table 5.

The structure of the mixed TFE solvated/hydrated form includes a cation, a chloride anion, and two neutrals, trifluoroethanol and a water molecule. In this structure, water molecules participate in H-bonds, but unlike the pentahydrate and trihydrate forms, they do not separate the charged atoms. TFE and water molecules played only the role of donors in the hydrogen bond network. Especially in water molecules, only one of the hydrogen atoms acts as a donor, which accounts for the irregularity of the water molecules and the non-stoichiometric ratio of water molecules to API molecules. It is thought that it has become.

Figure 44 shows the characteristic X-ray powder diffraction (XRPD) pattern of Form K ponatinib hydrochloride. The K-shaped XRPD pattern shown in FIG. 44 has angle 2 theta (2θ) peaks with relative intensities of 20% or more: 6.1; 7.4; 13.5; 17.4; 18.5; 20. 7; 23.9; and 28.3. In certain embodiments, Form K is characterized by an XRPD pattern that includes one or more of the following peaks 2 theta (2θ): 7.4 and 23.9. In certain embodiments, the XRPD pattern of Form K exhibits two peaks, three peaks, four peaks, or five peaks.

Characteristics of amorphous ponatinib hydrochloride:
Figure 45 shows the XRPD patterns of Form A ponatinib hydrochloride (bottom pattern) and amorphous ponatinib hydrochloride (top pattern) (solvent: 2,2,2-trifluroethanol). It is easily seen that Form A has a set of clearly distinguishable peaks at specific angles of 2-theta, whereas the amorphous form of ponatinib hydrochloride has no distinct peaks.

Additionally, amorphous ponatinib hydrochloride has a unique melting temperature compared to Form A amorphous ponatinib hydrochloride. FIG. 46 shows a characteristic differential scanning calorimetry (DSC) thermogram of amorphous ponatinib hydrochloride. A strong endothermic event was observed with a peak at 259.4°C, which corresponds to the melting point of the amorphous form. This melting point is different from that observed for Form A ponatinib hydrochloride, which had a melting point of 264.1°C.

The unique and different physical properties of amorphous ponatinib hydrochloride and Form A ponatinib hydrochloride do not appear to be due to the purity of the respective substances. For amorphous ponatinib hydrochloride, HPLC revealed the purity of the material to be 99.7877% (area percent) (see Figure 47), whereas the purity of form A ponatinib hydrochloride was found to be 99.8% (area percent).
Example

Example 1
Polymorph Discovery Initial efforts to discover polymorphs of ponatinib hydrochloride were divided into two stages. The first stage included starting material characterization, feasibility testing and solubility testing to provide data for selecting the second stage solvent. The second stage included 192 milliliter (ml) scale polymorphism screening experiments. From these initial efforts, eight polymorphs were discovered: Form A, Form B, Form C, Form D, Form E, Form F, Form G, and Form H.

Step 1: Starting Material Characterization Approximately 24 grams of the compound ponatinib hydrochloride was obtained as a pale yellow solid. The starting material was characterized by XRPD, digital imaging, DSC, TGMS and HPLC. Starting material, 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl ) Phenyl}benzamide monohydrochloride was obtained as a crystalline material (named HCl1), the chemical purity of which was estimated to be 99.8% by HPLC. TGA and TGMS analysis showed a 0.7% mass loss (residual ethanol) in the temperature range from 25°C to 240°C before the pyrolysis process. DSC analysis showed an endothermic event with T _peak = 264.8°C, which is associated with the compound 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[( This is believed to be due to melting and/or decomposition of 4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide monohydrochloride.

Stage 1: Solubility Testing Quantitative solubility testing of ponatinib hydrochloride starting material was performed using a set of 20 solvents. After preparing a slurry with an equilibration time of 24 hours, the slurry was filtered. Solubility was determined from saturated solutions by HPLC. The residual solids were characterized by XRPD. The results are summarized in Table 6.

In 19 of the experiments shown in Table 6, the material analyzed after solubility evaluation in 19 different solvents appeared to be in the same form as the starting material, designated HCl1. In experiment QSA13, performed with 2,2,2-trifluoroethanol, the material was completely dissolved at the selected concentration, resulting in an amorphous material from the sample obtained after solvent evaporation. The solids obtained from the two slurries in water (QSA12 and QSA21) resulted in two different forms, HCl2 and HCl2b, respectively. After several days of storage under ambient conditions, the HCl2 form converted to the HCl2b form and could not be characterized further. Further characterization revealed that form HCl2b is a hydrated form (API/water ratio 1:1.4).

Phase 1: Feasibility Study A feasibility study was conducted to attempt to obtain an amorphous starting material that could be used in some of the crystallization techniques of the second phase part of this study. Two techniques were used: milling and freeze drying. The results are shown below.

Grinding Two types of grinding experiments were carried out at a frequency of 30 Hz and for different durations. After milling for 60 minutes, the crystalline starting material converted to amorphous form. After 120 minutes, the material obtained remained amorphous and had a chemical purity of 99.6%.

Lyophilization 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl) Eight types of lyophilization experiments were conducted with phenyl}benzamide monohydrochloride. These experiments are summarized in Table 7.

The solubility of the compound ponatinib hydrochloride in tetrahydrofuran, 2-methyltetrahydrofuran and dichloromethane was too low to use the freeze-drying method under favorable conditions. Amorphous materials were obtained with solvents such as methanol, 2,2,2-trifluoroethanol (TFE) and TFE/water mixtures. In samples obtained from neat TFE or solvent mixtures with high TFE content, 11% residual solvent was detected in the dry powder (according to TGMS results). Samples obtained from methanol and TFE/water (50:50) had lower residual solvent contents, only 0.9% and 1.5%, respectively. Further drying for 24 hours was able to reduce the amount of residual solvent in the amorphous material produced from TFE/water (50:50) to less than 1%. Chemical purity was assessed as 99.8% by HPLC for both methanol and TFE/water (50:50) amorphous samples. Because creeping was observed in freeze-drying experiments with methanol, TFE/water (50 :50) was selected.

Step 2: Polymorph Discovery Six different crystallization methods: (1) cooling-evaporation; (2) antisolvent addition; (3) grinding; (4) slurry; (5) vapor diffusion into solution; and (6) performed polymorphic screening experiments of ponatinib hydrochloride on the milliliter (ml) scale using 192 different conditions using vapor diffusion onto a solid. After completing the screening experiment, material was collected and analyzed by XRPD and digital imaging.

Cooling-Evaporation Crystallization Experiments Thirty-six ml scale cooling-evaporation experiments shown in Table 8 were performed in 1.8 ml vials using 36 different solvents and solvent mixtures and one concentration. 25 mg of amorphous ponatinib hydrochloride was weighed into each vial. Screening solvent was then added until the concentration reached approximately 60 mg/ml. In addition, the vial containing the magnetic stirrer was capped and placed in the Avantium Crystal 16 to run the temperature profile (described in Table 9 below). The mixture was cooled to 5° C. and held at that temperature for 48 hours before the vial was placed under vacuum. Solvents were evaporated for several days at 200 mbar or 10 mbar and then analyzed by XRPD and digital imaging.

Crash crystallization experiments with addition of poor solvents For the rapid crystallization experiments, one solvent and 24 different poor solvents were used, and 36 different crystallization conditions were used (see Table 9). sea bream). The poor solvent addition experiment proceeded as follows. A stock solution was prepared and filtered into 8 ml vials after 24 hours of equilibration to reach the concentration of ponatinib hydrochloride at saturation at ambient temperature. A different antisolvent was added to each of these vials using a solvent to antisolvent ratio of 1:0.25. Since no precipitation occurred, this ratio was increased to 1:4 with a 60 minute wait time between additions. Since no precipitation still occurred, the solvent was completely evaporated at room temperature under vacuum. After evaporation, this experiment resulted in no yield.

Grinding experiment In the droplet grinding method, the raw material 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl] A small amount of solvent is added to -3-(trifluoromethyl)phenyl}benzamide monohydrochloride, and the mixture is ground in a stainless steel grinding jar containing two stainless steel grinding balls. In this way, the effects of 24 different solvents (see Table 10) were investigated. Typically, 30 mg of starting material was weighed into a grinding vessel and 10 μl of solvent was added to the vessel. Grinding experiments were conducted at 30 Hz for 120 minutes. Each wet material was then analyzed by XRPD and digital imaging.

Slurry Experiments A total of 48 slurry experiments were conducted using the compound ponatinib hydrochloride and 24 different solvents at 10°C and 30°C over a period of 2 weeks. Table 11 summarizes the experimental conditions. Experiments were carried out by stirring a suspension of substances in a solvent at a controlled temperature. At the end of the slurry time, the vial was centrifuged to separate the solids and mother liquor. The solid was further dried under full vacuum at room temperature and analyzed by XRPD and digital imaging.

Vapor Diffusion into Solution In this vapor diffusion experiment, a saturated solution of ponatinib hydrochloride was exposed to solvent vapor for two weeks at room temperature. A volume of the saturated solution was transferred to an 8 ml vial with the lid open, and 2 ml of the antisolvent was placed in a 40 ml vial with the lid closed (see Table 12). After two weeks, solid formation of the sample was confirmed. Drying the samples under vacuum (200 mbar or 10 mbar) resulted in no yield. Based on this result, new experiments were conducted under 12 different crystallization conditions listed in the table (experiment ID, VDL25 to VDL36).

Vapor Diffusion onto Solids In this vapor diffusion experiment, amorphous ponatinib hydrochloride was exposed to solvent vapor for two weeks at room temperature. The 8 ml vial containing the amorphous API was left open and placed in a 40 ml vial containing 2 ml of antisolvent and closed (see Table 13). After two weeks, the solids were analyzed by XRPD and digital imaging. If the solid was liquefied by vapor, the sample was dried under vacuum (200 mbar or 10 mbar) and then analyzed by XRPD and digital imaging.

These first effort crystallization experiments revealed seven new polymorphs in addition to the amorphous material and starting material Form A from XRPD analysis of the resulting dry (and wet, if applicable) samples. The existence of was revealed. These seven forms are named HCl2, HCl2b, HCl3 class, HCl5, HCl5b, HCl6 class and mixture HCl1+HCl4.

Figure 2 shows the incidence of various forms obtained in the second phase of these initial efforts. Representative XRPD patterns and digital images of each form obtained in these second stage experiments were obtained. Characterization of the shapes obtained in the first phase of these initial efforts is summarized in Table 14.

The polymorphisms identified in these first and second stage experiments and shown in FIG. 2 were primarily assigned by XRPD analysis. In the process of this analysis, we found that for some patterns, the general fingerprint of the was observed. These types of patterns were grouped together as classes of patterns (eg, HCl3 class). Based on XRPD, the similarity between the XRPD patterns within the class suggests that these solid forms are isomorphic hydrates/solvates (crystal packing is nearly the same, but different solvents into the crystal structure). The conclusion was that this is explained by the slight difference in unit cell parameters due to the incorporation of water and water incorporation.

Classes of isomorphic solvates were named by numbers (HCl3 class) or combinations of numbers and letters (eg, HCl2 and HCl2b). Isomorphic solvate/hydrate classes named by letter-number combinations indicate that several subclasses of this class have been observed in experiments (eg HCl2 and HCl2b). If four or more subclasses were identified within a class, all XRPD patterns corresponding to the isomorphic solvate/hydrate class were rearranged into one number (eg, HCl3 class).

Isomorphic solvates within a particular class or between classes named with the same number showed greater similarity in their XRPD patterns than classes of isomorphic solvates named with different numbers. The greater differences in the XRPD patterns of these different classes of isomorphic hydrates/solvates reflect significant differences in the packing ratio of the crystal structures.

In some XRPD patterns, one or two new peaks were observed compared to the identified forms. Since such peaks could not be unambiguously assigned to a known form, they were designated as "plus peaks."

Example 2
Further Polymorphic Discovery Subsequent efforts were carried out to obtain 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl) A single crystal of methyl]-3-(trifluoromethyl)phenyl}benzamide monohydrochloride was analyzed. Through these efforts, five different types of pseudopolymorphisms were discovered, and two of these new polymorphisms had not been discovered before. The two newly discovered polymorphisms are designated herein as HCl7 (also referred to herein as "Form J") and HCl8 (also referred to herein as "Form K"). In these subsequent experiments, three different crystallization methods were used: (1) gentle evaporation of the crystallization solvent; (2) 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl -N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide monohydrochloride solution; and (3) the temperature was controlled. Using crystallization, a single crystal of a size suitable for analysis was grown. In these subsequent experiments, a total of 54 crystallization experiments were performed to attempt to grow a single crystal of the hydrated form of ponatinib hydrochloride for structure determination.

For temperature-controlled crystallization, 24 experiments were set up using a mixture of alcohol and water (see Table 15). 10 mg of ponatinib hydrochloride was used in each experiment. The API and solvent mixture was rapidly heated up to 80°C and gently cooled to room temperature (0.1°C/min).

Regarding evaporative diffusion into solution, 25 experiments were performed. For each experiment, 10 mg of ponatinib hydrochloride was dissolved in 1 ml of TFE/water (10:90) or MeOH/water (30:70) mixture. Each solution was placed in a 6 ml vial, which was placed into a 20 ml vial containing 3 ml of antisolvent. The vial was stored at room temperature for 2-4 weeks. Details are reported in Table 16.

For gentle evaporation of solvent, 10 mg of ponatinib hydrochloride was placed in an 8 ml vial and 2 ml of solvent (mixture of solvents) was added. If the solids did not dissolve, the vial was heated to 90°C. The mixture was then allowed to cool gently to room temperature (see Table 17). For experiment 53 listed at the end of Table 17, the material was not completely dissolved even after several hours at 90°C.

Each of the polymorphs disclosed herein is made by a specific crystallization/solvent method using ponatinib HCl as a starting material. Although the synthesis of ponatinib HCl has been previously described (eg, WO 2007/075869 and WO 2011/053938), the following synthesis of ponatinib HCl is described in Example 6.

Example 3
Stress Testing of Form A Ponatinib Hydrochloride Form A is a crystalline, anhydrous solid obtained with high reproducibility from a variety of solvents. The HCl-1 form is inherently chemically stable, which correlates directly with the thermodynamic stability of the HCl1 form. The HCl-1 form is stable to temperature, pressure and humidity stresses and exposure to some solvent vapors and is thermodynamically stable. Numerous tests have been conducted to confirm its stability, both in the formulated state (tablets) and in the unformulated state (drug substance). The results of such tests are set forth in Table 18 below.

The HCl-1 form is stable to temperature, pressure and humidity stresses and exposure to solvent vapors and is the most thermodynamically stable solid form isolated to date.

To test the physical stability of crystalline HCl Form 1, experiments were conducted as follows.

Crystalline HCl1 form and a 50:50 physical mixture of HCl1 and amorphous material were exposed to ethanol vapor for 2 weeks (see Vapor Diffusion Experiments). Tablets were prepared by applying pressures of 50 kN/cm ² and 100 kN/cm ² (or 4 tons/cm ² and 8 tons/cm ² ) to crystalline HCl Form 1 for 10 seconds. Form A was stored in capsules under ambient conditions for up to 17 months. These samples were analyzed by high resolution XRPD.

The obtained results are summarized in Table 19, and XRPD measurement results and digital images were also obtained. These showed that the polymorphic HCl1 form did not change within the applied stress conditions, confirming its excellent physical stability.

Example 4
Stability of Specific Polymorphs Eight solid form samples of the HCl salt were selected and tested for their physical stability. Two representative samples of each relevant polymorph of the resulting HCl salt were selected. Each sample was analyzed again by XRPD. Physical stability of each form after storage for 8 months under ambient conditions. The results are summarized below:
The HCl1, HCl2b, HCl3, HCl5b and HCl6 classes are stable under the conditions studied;
HCl2 was converted to HCl2b (this conversion already occurred after 1 day of storage of the sample under ambient conditions);
HCl5 was converted to HCl5b (this conversion already occurred after 3 days of drying under full vacuum);
The mixture HCl1+HCl4 was converted to HCl1 after 8 months under ambient conditions.

Example 5
Preparation of Form A Ponatinib HCl is formed as a crystalline material by adding an ethanolic solution of HCl (1.0 equivalents) to an ethanolic solution of ponatinib free base. The drug substance ponatinib HCl crystallizes at the final stage of drug substance synthesis by the addition of seed crystals that give the drug substance a highly consistent and characteristic particle size and range. The ethanol content of the last 10 kilogram scale batches of HCl-1 ponatinib HCl was 0.8-1.2%.

Form A is anhydrous since there was no evidence of the presence of ethanol and water in Form HCl-1. Furthermore, the crystal packing of the HCl-1 form lacks voids that can accommodate small organic molecules, including ethanol. New studies examining ethanol content and removal of ethanol from ponatinib HCl during the drying process found that ethanol appears to bind to the crystal surface of Form A ponatinib HCl.

Form HCl-1 is characterized by the consistent presence of residual ethanol in the drug substance of all batches at a level of about 1% by weight. Crystallographic and other studies have shown that residual ethanol is present (trapped) at the crystal surface and is not part of the crystal unit cell, and that HCl-1 is not an ethanol solvate or a channel solvate. I found out that there isn't. Ethanol levels for the last 10 multi-kilogram scale drug substance batches were 0.8-1.2%.

II. The preparation of the polymorphic ponatinib free base starting material (AP23534) is illustrated and described in the synthesis section of this disclosure (see Scheme 1). The preparation of the amorphous free base is described in the section of this disclosure entitled "Feasibility Testing of Ponatinib Free Base Compounds" described below.

XRPD analysis revealed a total of 11 polymorphs of ponatinib originating from the ponatinib free base starting material, including anhydrous, hydrate, solvate, and isohydrate/solvate forms. These 11 new polymorphs are herein described as A, B (or B class), C, D, E (or E class), F, G, H (or H class type), I type, J type and K type.

Anhydrous form A (melting point around 200°C) was the main crystalline form seen in the screening. Form B contains four isomorphic solvates: 1:1 dioxane solvate, 1:1 perfluorobenzene solvate, 1:0.4 2-methylTHF solvate, and 1:1 cyclohexanone solvate. Contains things. Form E includes chloroform and dichloromethane isomorphic solvates. Form D is a solvate form (eg DMA). Form F is the monohydrate form. Form H includes two isomorphic solvates, a 1:0.6 1-propanol solvate and a 1:0.93 2-methoxyethanol solvate.

The shape assignments obtained in the third and fourth stage experiments were primarily based on XRPD analysis. From this analysis, we observed that some patterns show some slight differences such as peak shifts and/or another small peak, although the general fingerprint of the XRPD pattern is almost the same. We were able to. These types of patterns are grouped together as a pattern class (eg, B class). Based on XRPD, the similarity between the XRPD patterns within the class indicates that these solid forms are isomorphic hydrates/solvates (the crystal packing is nearly the same, but different solvents into the crystal structure). This may indicate that there are slight differences in the unit cell parameters due to the incorporation of water and water incorporation. Classes of isomorphic solvates were named by letter (B class).

In some XRPD patterns, one or more new peaks were observed compared to the various forms identified. Since such a peak could not necessarily be clearly assigned to a known form, it was expressed as a "plus peak" (for example, "F-form plus peak") as necessary.

The polymorphic screen for ponatinib included six different crystallization methods performed at the milliliter scale. These methods included: rapid crystallization with antisolvent addition; milling; slurry experiments; vapor diffusion into solution; cooling-evaporation crystallization; and vapor diffusion onto solids. These methods are described above for the preparation of various ponatinib hydrochloride polymorphs. Any differences in the method as applied to the ponatinib free base polymorphism are discussed below.

The crystal structures of Form A and two Type B solvates were determined by single crystal X-ray data analysis. This experiment revealed the conformation adopted by Form A in its crystal structure and the inclusion of solvent in two types of Form B solvates.

In general, these various crystalline forms of ponatinib disclosed herein have physical properties (such as increased stability) that are advantageous for solid dosage form commercial formulations compared to amorphous forms of ponatinib. Using the same types of physicochemical data (e.g., DSC, You can easily see the difference between them.

Figures 48 and 49 tabulate 10 of the 11 solid forms of ponatinib, including polymorphs and pseudopolymorphs identified as Forms A-J disclosed herein. (Form K is discussed separately later in the specification and is not part of the tables in this summary). Figures 48 and 49 summarize the origin, incidence and various characteristics of ponatinib polymorphisms.

With respect to FIG. 48, "LC" refers to low crystalline ponatinib (eg, Form C) used as a starting material for various other polymorphs. "A" refers to Form A, which is the most abundant crystalline form of ponatinib and can be used to prepare other forms by the various crystallization methods listed above. The footnotes listed in the table in Figure 48 are as follows:
(a) Classification by XRPD after completion of crystallization experiment;
(b) Crystallization methods: cooling-evaporation (PSM), rapid crystallization by addition of anti-solvent (AS), grinding (GRP), slurry (SLP), vapor diffusion onto solids (VDS) and vapor into solution. Diffusion (VDL). Freeze drying (FD) was used to generate the low crystallinity material (see experiment stage 3). QSA: Quantitative solubility experiment (third stage);
(c) Occ: The total occurrence rate includes 192 experiments performed in the fourth stage, in which 61 samples were further analyzed wet or by evaporation of the mother liquor, resulting in a total of 253 substances. The characteristics were evaluated. For example, "(6, 2.4%)" corresponds to the shape appearing 6 times out of 253 measurements and its percentage being 2.4%. For 4 out of 253 measurements (1.6%), the yield or scattering intensity of some products was too low to identify the solid form, or the material was wet;
(d) PO: favorable orientation effect; and (e) starting material: Form A or low crystallinity (LC) material obtained by lyophilization.

With regard to the above methodology used to evaluate the ponatinib hydrochloride polymorphism, 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4- Polymorphisms of methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide free base are described.

Characteristics of Form A Ponatinib Anhydrous Form A (same crystalline form as the starting material) was the main crystalline form discovered in the screen. The chemical structure of ponatinib Form A has been clearly established by single crystal X-ray crystallography. The observed solid form of ponatinib is Form A, an anhydrous crystalline solid.

Figure 50 shows the molecular structure and numbering scheme of Form A ponatinib free base compound (anhydride) obtained from single crystal X-ray diffraction. Based on this structural analysis, Form A was revealed to be the anhydride form.

Crystallographic data (collected up to θ=26°) for the anhydride Form A are listed in Table 21.

FIG. 51 shows a comparison of the experimental XRPD pattern of Form A and the calculated pattern based on the determined crystal structure (assuming FWHM=0.1°). The close similarity of the two XRPD patterns indicates that the crystal structure of Form A is representative of the bulk material.

In the XRPD pattern shown in FIG. 51, crystalline Form A has the following peaks at angles 2 theta (2θ): 6.2; 8.8; 9.9; 11.2; 12.3; 12.9; 13.5; 13.8; 14.2; 14.4; 16.0; 16.4; 17.2; 17.6; 18.0; 18.2; 19.3; 19.5; 19. 8; 20.6; 21.5; 21.9; 22.2; 22.6; 23.1; 24.0; 24.4; 25.1; 25.6; 25.9; 26.8; At least one or all of 27.4; 27.8; 29.1; and 29.8 are shown. In certain embodiments, Form A has the following peaks 2 theta (2θ): 6.2; 12.3; 13.8; 14.4; 16.0; 16.4; 17.2; 17 .6; 18.2; 19.5; 19.8; 20.6; 21.5; 22.2; 24.0; 25.9; 26.8; 27.4; characterized by an XRPD pattern including one or more. In the XRPD pattern shown in FIG. 51, shape A has the following 2-theta (2θ) peaks: 12.3; 13.8; 14.4; 17.6; 19.8; 20.6; 21. 5; 22.6; and 24.0. In certain embodiments, Form A has the following peaks 2 theta (2θ): 12.3; 13.8; 17.6; 19.8; 20.6; 21.5; 22.6; and 24.0. In certain embodiments, the XRPD pattern of Form A exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above. In certain embodiments, crystalline Form A of ponatinib free base is characterized by an XRPD pattern that is substantially similar to the top XRPD pattern of FIG. 51 (the resulting pattern). In certain embodiments, the crystalline Form A has a characteristic peak represented by the angle 2-theta shown in either the bottom (simulated pattern) or top (obtained pattern) pattern of FIG. includes an XRPD pattern with .

Referring to Figure 52, the melting point of ponatinib in anhydrous Form A was determined by differential scanning calorimetry (DSC). Two samples of ponatinib, AP24534 Lot 1285.206A (treated with 1-PrOH) and AP24524 Lot 1-PrOH untreated, were heated at a heating rate of 10 °C/min in a crucible with a small hole using a dry _N2 gas purge. , analyzed over a temperature range of 30°C to 350°C. An endothermic event was observed that peaked at 199.6°C, which corresponds to the melting point of Form A ponatinib.

Characteristics of Form B (class B) ponatinib polymorphism Characteristics of ponatinib/1,4-dioxane 1:1 solvation Form B 1:1 1,4-dioxane solvation using single crystal X-ray diffraction analysis The crystal structure of Form B was determined. Figure 53 shows the molecular structure and numbering scheme of 1:1 1,4-dioxane solvate Form B obtained from single crystal X-ray diffraction.

Crystallographic data (collected up to θ=27.4°) for the 1:1 1,4-dioxane solvate Form B are listed in Table 22.

Figure 54 shows the pattern of ponatinib/1,4-dioxane 1:1 solvate Form B calculated based on the determined crystal structure.

In the XRPD pattern shown in Figure 54, the ponatinib/1,4-dioxane 1:1 solvate Form B has the following peaks at 2 theta (2θ) angles: 5.6; 7.2; 9.8; 10. 8; 12.1; 12.5; 12.8; 14.5; 15.3; 15.8; 17.0; 17.3; 17.5; 18.5; 19.0; 19.5; 20.0; 20.3; 21.1; 21.6; 22.4; 22.8; 23.5; 24.1; 24.5; 25.3; 26.0; 26.4; 27. 0; 27.5; 28.4; 30.8; and 32.0. In certain embodiments, the ponatinib/1,4-dioxane 1:1 solvate Form B has the following peaks 2 theta (2θ): 5.6; 10.8; 12.1; 14.5; 15 .3; 15.8; 17.0; 17.3; 18.5; 19.0; 20.0; 20.3; 21.6; 22.4; 24.5; and 26.0. characterized by an XRPD pattern including one or more. In the XRPD pattern shown in Figure 54, the ponatinib/1,4-dioxane 1:1 solvate Form B has the following 2-theta (2θ) peaks: 5.6; 12.1; 14.5; 15. 3; 15.8; 17.3; 18.5; 19.0; 20.3; 21.6; and 26.0. In certain embodiments, the ponatinib/1,4-dioxane 1:1 solvated Form B has the following peaks 2 theta (2θ): 5.6; 14.5; 15.3; 15.8; 19 .0; 20.3; and 26.0. In certain embodiments, the XRPD pattern of ponatinib/1,4-dioxane 1:1 solvate Form B exhibits two peaks, three peaks, four peaks, or five peaks selected from the peaks described above. In certain embodiments, the ponatinib/1,4-dioxane 1:1 solvate Form B is characterized by an XRPD pattern that is substantially similar to the XRPD pattern of FIG. In certain embodiments, the ponatinib/1,4-dioxane 1:1 solvate Form B is crystalline.

Characteristics of Ponatinib/Perfluorobenzene 1:1 Solvate Form B The crystal structure of the 1:1 perfluorobenzene solvate Form B was determined using single crystal X-ray diffraction analysis. Figure 55 shows the molecular structure and numbering scheme of the 11:1 perfluorobenzene solvate Form B obtained from single crystal X-ray diffraction. The similarity in unit cell and crystal packing observed between 1,4-dioxane solvate and fluorobenzene solvate confirmed that these Form B class substances are isomorphic solvates.

Crystallographic data (collected up to θ=27.6°) for the 1:1 perfluorobenzene solvate Form B are listed in Table 23.

Figure 56 shows a comparison of the experimental XRPD pattern of Form B 1:1 perfluorobenzene solvate with the calculated pattern based on the determined crystal structure (assuming FWHM = 0.1°C). . The close similarity of the two XRPD patterns indicates that the crystal structure of Form B 1:1 perfluorobenzene is representative of the bulk material.

In the XRPD pattern of Figure 56, Form B 1:1 ponatinib/perfluorobenzene solvate has the following 2 theta (2θ) peaks: 7.0; 8.2; 9.8; 11.0; .5; 12.4; 12.8; 124.0; 14.4; 15.3; 16.0; 16.6; 17.2; 18.2; 19.0; 19.5; 20.0 ;20.1;21.1;22.0;22.5;22.7;23.5;24.0;24.5;25.1;26.0;27.0;27.8;28 .2; 31.8; and 35.4 are shown. In certain embodiments, Form B 1:1 ponatinib/perfluorobenzene solvate has the following peaks 2 theta (2θ): 5.6; 11.0; 12.4; 12.8; 14.4 ;15.3;16.0;16.6;17.2;18.2;19.0;20.1;22.0;22.5;22.7;23.5;24.5;26 .0; and 28.2. In the XRPD pattern shown in Figure 56, Form B 1:1 ponatinib/perfluorobenzene solvate has the following peaks at angles 2 theta (2θ): 5.6; 12.4; 15.3; 16.0; At least one or all of 19.0; 20.1; 22.0; 22.5; 22.7; and 26.0 are shown. In certain embodiments, Form B 1:1 ponatinib/perfluorobenzene solvate has the following peaks 2 theta (2θ): 5.6; 12.4; 15.3; 22.0; and 26. Characterized by an XRPD pattern that includes one or more of 0. In certain embodiments, the XRPD pattern of Form B 1:1 ponatinib/perfluorobenzene solvate exhibits two peaks, three peaks, four peaks, or five peaks. In certain embodiments, Form B 1:1 ponatinib/perfluorobenzene solvate is characterized by an XRPD pattern that is substantially similar to the top XRPD pattern of FIG. In certain embodiments, Form B 1:1 ponatinib/perfluorobenzene solvate is characterized by an XRPD pattern substantially similar to the XRPD pattern at the bottom of FIG. In certain embodiments, crystalline Form B includes a powder X-ray diffraction pattern with characteristic peaks represented by the angle 2-theta shown either at the top or bottom of FIG. 56.

Characteristics of ponatinib/cyclohexanone 1:1 solvate Form B and ponatinib/2-methylTHF 1:0.4 solvate Form B.
FIG. 57 shows a comparison of the XRPD patterns of two other B class forms and the XRPD pattern obtained with the A form. The upper pattern was obtained with 1:0.4 ponatinib/2-methylTHF solvate (B class, lyophilized, solvent=2-methylTHF), GEN8.1. The middle pattern was obtained with 1:1 ponatinib/cyclohexanone solvate (B class, solvent=cyclohexanone), QSA7.1. The lower pattern was obtained with anhydride Form A.

In the upper XRPD pattern shown in Figure 57, Form B 1:0.4 ponatinib/2-methylTHF solvate has the following peaks at angles 2 theta (2θ): 5.6; 9.5; 10. 5; 11.2; 12.0; 12.5; 13.5; 14.0; 15.0; 15.5; 16.2; 16.8; 17.0; 18.1; 18.8; At least one or all of 20.1; 21.2; 22.1; 26.0; 26.1; 27.5; and 28.2 are shown. In certain embodiments, Form B 1:0.4 ponatinib/2-methyl THF solvate has the following peaks 2 theta (2θ): 5.6; 12.0; 14.0; 15.0 15.5; 16.8; 18.1; 20.1; and 26.0. In the upper XRPD pattern shown in Figure 57, Form B 1:0.4 ponatinib/2-methylTHF solvate has the following peaks at angles 2 theta (2θ): 5.6; 12.0; 14. At least one or all of 0; 20.1; 22.1 and 26.0 are shown. In certain embodiments, Form B 1:0.4 ponatinib/2-methylTHF solvate has the following peaks 2 theta (2θ): 5.6; 14.0; 20.1; and 26. Characterized by an XRPD pattern that includes one or more of 0. In certain embodiments, the XRPD pattern of Form B 1:0.4 ponatinib/2-methylTHF solvate comprises two peaks, three peaks, four peaks, or five peaks selected from the peaks described above. show. In certain embodiments, Form B 1:0.4 ponatinib/2-methylTHF solvate is characterized by an XRPD pattern that is substantially similar to the top XRPD pattern of FIG. In certain embodiments, crystalline Form B includes a powder X-ray diffraction pattern with characteristic peaks represented by the angle 2 theta shown in the upper pattern of FIG.

In the center XRPD pattern shown in Figure 57, Form B 1:1 ponatinib/cyclohexanone solvate has the following 2-theta (2θ) peaks: 5.6; 9.5; 11.0; 12.0. ;12.9;14.0;15.2;16.2;16.8;17.0;18.1;18.8;19.5;20.1;21.8;22.3;23 24.5; 26.1; 27.5; 28.0; and 28.2 are shown. In certain embodiments, Form B 1:1 ponatinib/cyclohexanone solvate has the following peaks 2 theta (2θ): 5.6; 11.0; 12.0; 12.9; 14.0; 15.2; 16.8; 18.1; 18.8; 20.1; 21.8; 22.3; 24.5; and 26.1. do. In the center XRPD pattern shown in Figure 57, Form B 1:1 ponatinib/cyclohexanone solvate has the following 2-theta (2θ) peaks: 5.6; 14.0; 15.2; 16.8 ; 20.1; 21.8; 22.3; and 26.1. In certain embodiments, Form B 1:1 ponatinib/cyclohexanone solvate has the following peaks 2 theta (2θ): 5.6; 14.0; 15.2; 16.8; 20.1; 22.3; and 26.1. In certain embodiments, the XRPD pattern of Form B 1:1 ponatinib/cyclohexanone solvate exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above. In certain embodiments, Form B 1:1 ponatinib/cyclohexanone solvate is characterized by an XRPD pattern that is substantially similar to the center XRPD pattern of FIG. In certain embodiments, crystalline Form B includes a powder X-ray diffraction pattern with characteristic peaks represented by the angle 2-theta shown in the center pattern of FIG.

Figure 58 is a DSC curve obtained with B class 1:1 ponatinib/cyclohexanone solvate (QSA7.1), with endothermic events at T _peak = 110.1°C and T _peak = 198.6°C.

Figure 59 is a plot showing the TGA and SDTA thermograms of B class 1:1 ponatinib/cyclohexanone solvate (QSA7.1).

TGMS data for B class 1:1 ponatinib/cyclohexanone solvate (QSA7.1) shows 14.8% (cyclohexanone and water) and 0.0% water occurring within the temperature ranges of 50-160°C and 160-210°C, respectively. It showed a mass loss of 2% (cyclohexanone). Ponatinib/cyclohexanone was estimated to be approximately 1.0/0.96 from TGMS data.

Experiments were performed to determine the purity of B class 1:1 ponatinib/cyclohexanone solvate (QSA7.1) using HPLC. HPLC revealed the purity of B class 1:1 ponatinib/cyclohexanone solvate (QSA7.1) to be 99.7460% (area percent).

Figure 60 is a DSC curve obtained with B class 1: 0.4 ponatinib/2-methylTHF solvate (GEN8.1), with endotherms at T _peak = 67.1°C and T _peak = 197.5°C. An event is observed.

Figure 61 is a plot showing the TGA and SDTA thermograms of B Class 1:0.4 ponatinib/2-methylTHF solvate (GEN8.1).

B class 1: TGMS data for 0.4 ponatinib/2-methylTHF solvate (GEN8.1) indicates that 3.1 occurs within the temperature ranges of 40-90°C, 90-165°C and 165-215°C, respectively. % (2-methylTHF), 1.9% and 1.0% (2-methylTHF). The ponatinib/2-methylTHF ratio was estimated to be approximately 1.0/0.4 from TGMS data.

Experiments were performed to determine the purity of B class 1:0.4 ponatinib/2-methylTHF solvate (GEN 8.1) using HPLC. HPLC revealed a purity of 99.5939% (area percent) for B class 1:0.4 ponatinib/2-methylTHF solvate (GEN 8.1).

Characteristics of the Form C Ponatinib (Low Crystalline) Polymorph The less crystalline Form C can be obtained from the crystalline Form A in the solvent methanol in slurry experiments. Form C was found to contain solvated methanol at a ponatinib/methanol ratio of approximately 1:0.2.

Figure 62 is a DSC curve obtained for low crystallinity Form C (GEN3.1), with an endothermic event at T _peak = 95.9°C, an exothermic event at T _peak = 135.3°C, and T _peak = 198.1 An endothermic event is observed at ℃.

Figure 63 is a plot showing the TGA and SDTA thermograms of low crystallinity Form C (GEN3.1).

TGMS data for Form C (GEN3.1) showed a 1.3% mass loss (methanol) occurring within the temperature range 40-150°C. The ponatinib/methanol ratio was estimated to be approximately 1.0/0.2 from TGMS data.

Form C was analyzed by X-ray powder diffraction (XRPD). Figure 64 shows the XRPD pattern of the superimposed XRPD of the starting materials crystalline Form A (bottom pattern) and less crystalline Form C (top pattern).

In the upper XRPD pattern shown in Figure 64, the C-shape has the following peaks at angles 2 theta (2θ): 3.2; 11.1; 11.7; 12.8; 13.3; 13.5; At least one or all of 14.2; 17.1; 18.2; 20.8; 22.3; and 26.5 are shown. In certain embodiments, Form C has the following peaks 2 theta (2θ): 3.2; 12.8; 14.2; 17.1; 18.2; 20.8; 22.3 and 26 .5. In the XRPD pattern shown in Figure 64, the C-shape exhibits at least one or all of the following 2-theta (2θ) peaks: 3.2; 12.8; 14.2; and 18.2. has been done. In certain embodiments, the XRPD pattern of Form C exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above. In certain embodiments, Shape C is characterized by an XRPD pattern that is substantially similar to the top XRPD pattern of FIG. In certain embodiments, crystalline Form C includes a powder X-ray diffraction pattern with characteristic peaks represented by the angle 2 theta shown in FIG.

Experiments were conducted to determine the purity of Form C (GEN3.1) using HPLC. HPLC revealed the purity of Form C ponatinib to be 99.5725% (area percent).

Characteristics of Form D Ponatinib Polymorph Form D can be obtained from crystalline Form A by rapid crystallization in N,N-dimethylacetamide (DMA) with addition of an antisolvent. Form D thus produced was found to be a DMA solvate with a ponatinib/DMA ratio of approximately 1:1.

Figure 65 is a DSC curve obtained for type D (GEN5.1R1), in which endothermic events are seen at T _peak = 103.3°C, T _peak = 125.6°C, and T _peak = 198.4°C.

Figure 66 is a plot showing the TGA and SDTA thermograms of low crystallinity Form D (GEN5.1R1).

TGMS data for Form D (GEN5.1R1) showed a 13.8% mass loss (N,N-dimethylaceamide) occurring within the temperature range of 40-140°C. The ponatinib/DMA ratio was estimated to be approximately 1.0/0.98 from TGMS data.

Form D was analyzed by X-ray powder diffraction (XRPD). Figure 67 shows (from bottom to top) the XRPD patterns of the starting material crystalline Form A; Form D (GEN5.1R1); and the XRPD remeasurement 3 days later (GEN5.1R4) superimposed. , the analyzed samples may contain B class forms as well as D forms.

In the center XRPD pattern shown in Figure 67, the D-shape has the following 2-theta (2θ) peaks: 6.2; 8.0; 10.8; 11.5; 12.4; 13.5; 13.8; 14.5; 15.6; 16.5; 17.6; 18.5; 19.3; 19.8; 20.1; 20.8; 21.6; 22.1; 23. 8; 26.0; 27.1; and 29.6 are shown. In certain embodiments, Form D has the following peaks 2 theta (2θ): 6.2; 10.8; 12.4; 13.8; 14.5; 15.6; 16.5; 18 20.2; 20.8; 21.6; 26.0; and 27.1. In the center XRPD pattern shown in Figure 67, the D-shape has the following 2-theta (2θ) peaks: 6.2; 12.4; 14.5; 15.6; 16.5; 18.5; At least one or all of 20.2; 20.8; 21.6; 26.0; and 27.1 are shown. In certain embodiments, Form D has the following peaks 2 theta (2θ): 6.2; 15.6; 16.5; 18.5; 20.2; 21.6; 26.0; and 27.1. In certain embodiments, the XRPD pattern of Form D exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above. In certain embodiments, Form D ponatinib is characterized by an XRPD pattern that is substantially similar to the center XRPD pattern of FIG. 67. In certain embodiments, crystalline Form D includes a powder X-ray diffraction pattern with characteristic peaks represented by the angle 2 theta shown in FIG.

Experiments were performed to determine the purity of Form D using HPLC. HPLC revealed the purity of Form D ponatinib to be 99.5056% (area percent).

Characteristics of Form E (E-class) ponatinib polymorphism E-class solvents can be used to form crystals in slurry and solubility experiments with solvents such as tetrahydrofuran (THF), chloroform and dichloromethane (DCM), or by vapor diffusion onto solids. It is prepared from either the highly crystalline Form A or the less crystalline Form C.

Based on thermal analysis, one representative sample of Form E was solvated in ponatinib/tetrahydrofuran (THF) 1:1. Another representative sample of Form E appears to be the chloroform solvate, but this material was not further characterized except by XRPD.

Figure 68 is a DSC curve obtained with E-clasponatinib/THF 1:1 solvate (GEN7.1), with endothermic events at T _peak =95.9°C and T _peak =198.1°C.

Figure 69 is a plot showing the TGA and SDTA thermograms of E-clasponatinib/THF 1:1 solvate (GEN7.1).

TGMS data for E-clasponatinib/THF 1:1 solvate (GEN7.1) showed a mass loss of 11.7% (THF) occurring within the temperature interval of 40-130°C. The ponatinib/THF ratio was estimated to be approximately 1.0/0.98 from TGMS data.

The above two class E polymorphs were analyzed by X-ray powder diffraction (XRPD). Figure 70 overlays (from bottom to top) starting material crystalline Form A; E clasponatinib/THF 1:1 solvate (GEN7.1); and E clasponatinib/chloroform solvate (SLP3.1). The XRPD pattern of the combined XRPD is shown.

In the upper XRPD pattern shown in Figure 70, E clasponatinib/THF 1:1 solvate (GEN7.1) has the following peaks at angles 2 theta (2θ): 6.2; 7.0; 10.0. 13.0; 15.1; 16.4; 17.2; 18.5; 20.4; 20.5; 22.5; 24.4; 25.6; and 27.0. One or all are shown. In certain embodiments, E-clasponatinib/THF 1:1 solvate (GEN7.1) has the following peaks 2 theta (2θ): 6.2; 7.0; 10.0; 15.1; 16.4; 17.2; 18.5; 20.4; 20.5 24.4; and 27.0. In the upper XRPD pattern shown in Figure 70, E clasponatinib/THF 1:1 solvate (GEN7.1) has the following peaks at angles 2 theta (2θ): 6.2; 15.1; 16.4 ; 17.2; 18.5; 20.4; 24.4; and 27.0. In certain embodiments, E-clasponatinib/THF 1:1 solvate (GEN7.1) has the following peaks 2 theta (2θ): 6.2; 15.1; 16.4; 20.4; and 20.5. In certain embodiments, the XRPD pattern of E-clasponatinib THF 1:1 solvate (GEN7.1) exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above. In certain embodiments, the E-clasponatinib/THF 1:1 solvate is characterized by an XRPD pattern that is substantially similar to the XRPD pattern at the top of FIG. In certain embodiments, crystalline Form E includes a powder X-ray diffraction pattern with characteristic peaks represented by the angle 2 theta shown in the top pattern of FIG.

In the center XRPD pattern shown in Figure 70, E-clasponatinib/chloroform solvate (SLP3.1) has the following peaks at angles 2 theta (2θ): 6.2; 7.0; 8.7; 9. 8; 12.1; 12.5; 13.0; 15.2; 16.4; 17.2; 18.5; 20.0; 21.0; 23.0; 24.4; 25.0; and 26.2 are shown. In certain embodiments, E-clasponatinib/chloroform solvate (SLP3.1) has the following peaks 2 theta (2θ): 6.2; 7.0; 13.0; 15.2; 16.4 17.2; 18.5; 20.0; 21.0; 24.4; 25.0; and 26.2. In certain embodiments, the XRPD pattern of E-clasponatinib/chloroform solvate (SLP3.1) exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above. In certain embodiments, E-clasponatinib/chloroform solvate is characterized by an XRPD pattern substantially similar to the center XRPD pattern of FIG. 70. In certain embodiments, crystalline Form E includes a powder X-ray diffraction pattern with characteristic peaks represented by the angle 2 theta shown in the center pattern of FIG.

Experiments were performed to determine the purity of E-clasponatinib/THF 1:1 solvate (GEN7.1) using HPLC. HPLC revealed that the purity of the E-class ponatinib THF 1:1 solvate of ponatinib (GEN7.1) was 99.5120% (area percent).

Characteristics of Form F Ponatinib Polymorphism Form F is formed from Form A under certain experimental conditions, such as in the presence of polar solvents. Analysis of Form F by TGMS showed that Form F lost 3.3% water in the initial temperature range of 25-140°C. From these results, it was possible to infer that the first endothermic event observed corresponds to a dehydration process and that form F is a hydrated form, for example a 1:1 hydrate with water.

From the screening experiment, selected samples of pure form F (six samples) and mixtures of forms A and F (six samples) were stored at ambient temperature for 4 months and then analyzed again by XRPD. The results are shown in Table 24 below.

The results in Table 24 show that the polymorphisms remain unchanged in most cases. The results obtained in the poor solvent rapid crystallization experiments (2-methoxyethanol/water) indicate that the obtained form F substance converts to form A after 4 months when the sample is collected in a wet state. It was showing. Also, in a poor solvent addition experiment using acetone/water, Form F was converted to a mixture of Forms A and F after 4 months.

Figure 71 shows the TGA and SDTA plots obtained for type F (AS16.2). Form F (AS16.2) exhibited an initial endotherm followed by recrystallization in the temperature range 130-140°C. The melting point of Form F (AS16.2) was observed at approximately 189°C.

As mentioned above, TGMS data for Form F (AS16.2) showed a 3.3% mass loss (water) occurring within the temperature range of 25-140°C. The ponatinib/water ratio of Form F was estimated to be approximately 1.0/1.01 from TGMS data.

Form F (SLP10.1) was analyzed by X-ray powder diffraction (XRPD). In FIG. 83, a large number of XRDP patterns are shown stacked up, and in this figure, the F-type (SLP10.1) pattern is the fifth pattern from the top. This sample (SLP10.1) was obtained in a slurry experiment using 1,2-dimethoxyethane as the solvent.

In the XRPD pattern shown as the fifth pattern from the top of FIG. 83, Form F ponatinib has the following 2-theta (2θ) peaks: 7.2; 13.2; 14.1; 15.9; 18. 1; 20.4; 21.1; 22.0; 23.5; 24.2; 25.5; and 26.8. In certain embodiments, Form F has the following peaks 2 theta (2θ): 7.2; 13.2; 14.1; 15.9; 18.1; 20.4; 23.5; 25 .5 and 26.8. In the XRPD pattern shown as the fifth pattern from the top in FIG. 83, the F-shape has the following 2-theta (2θ) peaks: 7.2; 14.1; 18.1; 20.4; 25.5 ; and 26.8 are shown. In certain embodiments, the XRPD pattern of Form F exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above. In certain embodiments, Form F ponatinib is characterized by an XRPD pattern that is substantially about the same as the fifth XRPD pattern from the top of FIG. In certain embodiments, crystalline Form F includes a powder X-ray diffraction pattern with a characteristic peak represented by the angle 2 theta shown in the fifth pattern from the top of FIG.

Characteristics of Form H (class H) ponatinib polymorphism Characteristics of ponatinib/1-propanol 1:1 solvation Form H The solid recovered from the dissolution experiment using 1-propanol is the 1-propanol solvent of Form H It was revealed that it was a Japanese product.

The DSC curve obtained with H-clasponatinib/1-propanol solvate (SAS35) showed an endothermic event appearing with a T _peak of about 93°C and a T _peak of about 192°C.

TGMS data for H-clasponatinib/1-propanol solvate (SAS35) showed a 9.2% mass loss (1-propanol) occurring within the temperature interval of 25-120°C. The ponatinib/1-propanol ratio was estimated to be approximately 1.0/0.9 for H-clasponatinib/1-propanol solvate (SAS35) from TGMS data. In another sample (SAS30), a mass decrease corresponding to the 1:0.6 solvate was observed, but this sample was converted and partially returned to the crystalline anhydride form A, which was observed in the bulk sample. It was later revealed that the overall solvent reduction achieved was lower.

When the H class solvate (SAS35) was analyzed by powder X-ray diffraction (XRPD), the following peaks at the angle 2 theta (2θ) were found: 6.1; 6.8; 10.0; 12.0; 13 .2;13.5;16.0;16.5;16.0;16.5;18.0;19.0;19.5;20.4;21.0;22.5;25.0 ; 25.5; 26.2; 27.0; and 27.5. In certain embodiments, Form H has one of the following peak 2 theta (2θ): 12.0; 13.2; 13.5; 18.0; 25.0 and 25.5 or Features a plurality of XRPD patterns. In certain embodiments, the XRPD pattern of Form H exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above.

Characteristics of Ponatinib/2-Methoxyethanol 1:1 Solvated Form H Ponatinib free base can be formed from isomorphic solvates of Form H in other alcohols. Starting from the starting material Form A, the 2-methoxyethanol solvate was obtained by vapor diffusion into the liquid using 2-methoxyethanol as the solvent. The purity of this form was estimated to be 98.0%. TGMS confirmed this to be a 1:0.93 ponatinib/2-methoxyethanol solvate and desolvated at approximately 96°C. After desolvation, a melting point of about 198.8° C., approximately corresponding to that of Form A, was observed in DSC.

In the DVS experiment, a weight loss of about 3.6% was observed upon desorption, but it did not return to the original weight upon sorption to 45% RH. XRPD analysis at the end of the DVS experiment showed no physical changes. Although partial desolvation may have occurred, this process did not cause collapse of the crystal structure (as indicated by the approximately 12% weight loss observed by TG-MS upon desolvation). ).

However, form H was converted to form A after 1 week of accelerated stress conditions (40°C, 75% RH) in a humidity chamber, as well as during 10 months of storage under ambient conditions. .

Figure 72 is a DSC curve obtained for Form H (VLD1, dry solid from stock) with an endothermic event at T _peak = 96.1°C (desolvation event) and T _peak = 198.8°C. . The endothermic event at 198.8°C appears to be a Form A melting event.

Figure 73 is an overlay of characteristic TGA and SDTA thermograms of Form H (VLD1, dry solid from stock).

DVS experiments on Form H (VLD1, dry solid from stock) showed a weight loss of approximately 11.7% (2-methoxyethanol) in the temperature range 25-120°C. These results indicate that the first endothermic event observed corresponds to a desolvation process and that Form H (VLD1, dry solid from stock) is a 1:0.93 ponatinib/2-methoxyethanol solvent. It was Japanese food.

Figure 74 shows a series of XRPD patterns obtained on various samples of Form H ponatinib, along with the XRPD of Form A. In Figure 74: Plot 1 is H-form (VLD2 experiment, 2 weeks and after drying); Plot 2 is H-form (VLD1 experiment, 2 weeks and after drying); Plot 3 is H-form (VLD1 experiment, DVS Plot 4 is Form H (VLD1, dry solid from stock); Plot 5 is Form H (VLD19); bottom plot is XRPD of Form A. be. The XRPD patterns shown as plots 1-5 are substantially similar.

In the XRPD pattern shown as plot 5 in Figure 74, Form H ponatinib has the following peaks at angles 2 theta (2θ): 6.2; 6.5; 10.1; 12.0; 13.2; 15. 0; 15.5; 16.0; 16.5; 18.0; 19.1; 19.6; 20.5; 21.1; 23.0; 23.7; and 25.5. One or all are shown. In certain embodiments, Form H has the following peaks 2 theta (2θ): 6.2; 12.0; 13.2; 16.0; 18.0; 19.1; 19.6; 20 .5; 21.1; 23.0; and 25.5. In the XRPD pattern shown as plot 5 in FIG. everything is shown. In certain embodiments, the XRPD pattern of Form H exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above. In certain embodiments, Form H ponatinib is characterized by an XRPD pattern substantially similar to any one of patterns 1-5 of FIG. 74. In certain embodiments, the crystalline Form H includes a powder X-ray diffraction pattern having a characteristic peak represented by an angle 2 theta as shown in any one of patterns 1-5 of FIG.

Experiments were performed to determine the purity of Form H (VLD1 dry solid from stock) using HPLC. HPLC revealed the purity of Form H ponatinib (VLD1 dry solid from stock) to be 98.0464% (area percent).

Figure 75 shows a superposition of the characteristic FT-IR spectrum obtained from Form H ponatinib (VLD1 dried from stock) (Plot 1) and the FT-IR spectrum obtained from Form A (Plot 2). It is something. The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ).

Figure 76 shows the characteristic FT-IR spectra obtained from Form H ponatinib (VLD1 dried from stock) (Plot 1) and the FT-IR spectrum obtained from Form A (Plot 2) at wavelengths 1750-600 nm. It is a superposition of the regions of . The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ). In this superposition, a plurality of peaks characteristic of the H-form as well as a plurality of peaks characteristic of the A-form are recognized. In this regard, some peaks characteristic of form A (plot 2) in Figure 76 are: 1605 cm ^-1 ; 1415 cm ^-1 ; 1295 cm ^{-1 ;} 1250 cm ^{-1 ;} 1150 cm ^-1 ; 1100 cm ⁻¹ ; 895 cm ⁻¹ ; 855; and 790 cm ⁻¹ .

Characteristics of Form I ponatinib low crystallinity polymorphism Low crystallinity Form I was obtained by lyophilization technique in dichloromethane (DCM).

Based on thermal analysis, Form I (GEN9.1) contains insignificant levels of solvated DCM, corresponding to a ponatinib/DCM ratio of approximately 1:0.03.

FIG. 77 is a DSC curve obtained for Form I (GEN9.1), in which an exothermic event is observed at T _peak =100.1°C and an endothermic event is observed at T _peak =196.7°C.

Figure 78 is a plot showing the TGA and SDTA thermograms of Form I (GEN9.1).

TGMS data for Form I (GEN9.1) showed a 0.5% mass loss (DCM) occurring within the temperature range 40-175°C (slightly solvated). The ponatinib/DCM ratio was estimated to be approximately 1.0/0.03 from TGMS data.

Form I (GEN9.1) was analyzed by X-ray powder diffraction (XRPD). Figure 77 shows (from bottom to top) an XRPD superimposition of the starting materials crystalline Form A and Form I (GEN9.1).

In the upper XRPD pattern shown in Figure 79, the peaks at the angles 2 theta (2θ) listed below for the I-form (GEN9.1) are: 6.5; 8.2; 9.8; 14.3; 15.5 ; 17.5; 21.2; 23.1; and 26.5. In certain embodiments, Form I (GEN9.1) has the following peak 2 theta (2θ): 6.5; 8.2; 9.8; 14.3; 15.5; 17.5; 21.2; and 26.5. In the upper XRPD pattern of Figure 79, the I-form (GEN9.1) has the following angle 2-theta (2θ) peaks: 6.5; 8.2; 15.5; 17.5; 21.2; 26.5 are shown. In certain embodiments, Form I (GEN9.1) is characterized by an XRPD pattern that includes one or more of the following peaks 2 theta (2θ): 8.2; and 15.5. In certain embodiments, the XRPD pattern of Form I (GEN 9.1) exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above. In certain embodiments, Form I ponatinib is characterized by an XRPD pattern substantially similar to the top pattern of FIG. 79. In certain embodiments, crystalline Form I includes a powder X-ray diffraction pattern with characteristic peaks represented by the angle 2-theta shown in the top pattern of FIG. 79.

Experiments were performed to determine the purity of Form I (GEN9.1) using HPLC. HPLC revealed the purity of Form I (GEN9.1) ponatinib to be 99.5802% (area percent).

Characteristics of Form J ponatinib polymorph Form J was obtained by vapor diffusion onto solids. Purity was estimated to be 96.5%. From TGMS analysis (11.4% weight loss of thiophene in the interval 25-130°C), Form J "low crystallinity" desolvates at 83.7°C with a 1:0.82 ponatinib/thiophene solvation. It was confirmed that it was a thing. After desolvation, a melting point event occurs at about 197.3°C, which appears to be Form A melting.

In the DVS experiment, a weight loss of about 1.3% was observed during desorption. It appears that the sorption phase does not regain weight until at least 45% relative humidity (RH) (mass uptake is approximately 0.33%). XRPD analysis at the end of the DVS experiment showed that the material had converted to form A.

The low crystalline form J also converted to form A after 10 months of storage under ambient conditions and 1 week under stress conditions (40° C., 75% RH).

Two samples of Form J ponatinib (named VDS2 and VDS10 for screening S10010A) were analyzed by X-ray powder diffraction (XRPD). Figure 78 shows a superposition of the XRPD patterns (from top to bottom): Plot 6 is the XRPD pattern of form A (VDS2, after stability testing); Plot 7 is the XRPD pattern of form J (VDS2) Plot 8 is the XRPD pattern of Form J (VDS10 of Screening S10010A); Plot 9 is another XRPD pattern of Form A ponatinib.

In XRPD plots 7 and 8 of Figure 80, form J ponatinib has the following peaks at angles 2 theta (2θ): 5.8; 7.0; 12.1; 15.1; 16.8; 18.1; 18.6; 19.1; 19.5; 20.1; 21.1; 21.8; 22.8; 25.0; 25.7; and 27.0. has been done. In certain embodiments, Form J ponatinib has the following peak 2 theta (2θ): 5.8; 7.0; 12.1; 15.1; 16.8; 18.1; 19.1; 21.8; 22.8; 25.0; 25.7; and 27.0. In the upper XRPD pattern of Figure 80, Form J ponatinib has the following 2-theta (2θ) peaks: 5.8; 7.0; 12.1; 15.1; 16.8; 18.6; 19 .1; 19.5; 21.8; 22.8; 25.0; 25.7; and 27.0. In certain embodiments, Form J ponatinib has the following peak 2 theta (2θ): 5.8; 7.0; 12.1; 15.1; 18.6; 19.5; 21.8; 25.0; 25.7; and 27.0. In certain embodiments, the XRPD pattern of Form J ponatinib exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above. In certain embodiments, Form J ponatinib is characterized by an XRPD pattern that is substantially similar to either of plots 7 and 8 of FIG. In certain embodiments, the crystalline Form J comprises a powder X-ray diffraction pattern having a characteristic peak represented by the angle 2-theta shown in either plot 7 or 8 of FIG.

Experiments were conducted to determine the purity of Form J (VDS2) using HPLC. HPLC revealed the purity of Form J (VDS2) ponatinib to be 96.4509% (area percent).

Figure 81 shows the characteristic FT-IR spectrum obtained from Form J (VDS2) ponatinib (Plot 1) superimposed with the FT-IR spectrum obtained from Form A (Plot 2). The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ).

Figure 82 shows the superimposition of the characteristic FT-IR spectrum obtained from Form J (VDS2) ponatinib (Plot 1) and the FT-IR spectrum obtained from Form A (Plot 2) in the wavelength range of 1750 to 600 nm. It is something that The vertical axis shows the percent transmittance (%), and the horizontal axis shows the wave number (cm ⁻¹ ).

Characteristics of Form K Ponatinib Polymorph Solid Form K was found in sample SAS58 (MSZW experiment) at 25 mg/mL in 1-propanol/acetonitrile (30/70). The TGMS thermogram showed negligible mass loss (less than 0.04% in the temperature interval 25-175° C.) before melting. From the SDTA signal, the melting point of Form K is 184°C.

The DSC curve obtained with Form K of ponatinib showed an endothermic event appearing at a T _peak of approximately 184°C.

When Form K ponatinib was analyzed by X-ray powder diffraction (XRPD), the following peaks at the angle of 2 theta (2θ) were found: 10.0; 11.0; 13.4; 14.6; 15.2; 16. 0; 17.0; 17.5; 18.0; 19.6; 20.9; 22.1; 22.8; 24.1; 24.8; 26.5; 27.1; 28.5; and 30.5 appeared. In certain embodiments, Form K has the following peaks 2 theta (2θ): 10.0; 11.0; 13.4; 14.6; 15.2; 16.0; 19.6; 20 .9; 22.1; 22.8; 24.1; 24.8; and 26.5. In certain embodiments, Form K has the following peaks 2 theta (2θ): 10.0; 11.0; 13.4; 14.6; 15.2; 19.6; 22.1; 22 .8; and 24.1. In certain embodiments, the XRPD pattern of Form K exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above.

Overlay of XRPD patterns of selected ponatinib polymorphisms Figure 83 is an overlay of XRPD results obtained with selected ponatinib free base polymorphisms. The XRPD patterns shown are from bottom to top: Form A (SM); Class B (QSAS7.1); Form C, low crystallinity (GEN3.1); Form D (GEN5.1); Class E (SLP3.1); Form F (SLP10.1); Form G (AS19.1), described later herein; Form H (VDL19.1); Form I, low crystallinity (GEN9.1); and It was obtained with J type and low crystallinity (VDS10.1).

Characteristics of Form G Ponatinib Polymorphism Figure 83 illustrates Form G ponatinib obtained by a rapid crystallization/anti-solvent process, in which the solvent used was 3-methyl-1-butanol; The poor solvent is cyclohexane. When Form G ponatinib was analyzed by powder X-ray diffraction (XRPD), the following peaks at the angle 2 theta (2θ) were found: 5.0; 6.5; 9.5; 12.0; 12.5; 14. 0; 15.0; 16.5; 17.2; 18.4; 20.0; 21.0; 22.8; 23.5; 24.6; and at least one or all of 29.5 appeared. In certain embodiments, Form G has the following peaks 2 theta (2θ): 5.0; 6.5; 9.5; 14.0; 15.0; 16.5; 17.2; 18 .4; 20.0; and 22.8. In certain embodiments, Form G has the following peaks 2 theta (2θ): 5.0; 6.5; 9.5; 14.0; 17.2; 18.4; 20.0; and 22.8. In certain embodiments, the XRPD pattern of Form G exhibits 2 peaks, 3 peaks, 4 peaks, or 5 peaks selected from the peaks described above. In certain embodiments, Form G ponatinib is characterized by an XRPD pattern that is substantially similar to the fourth pattern from the top of the superimposed pattern of FIG. 83. In certain embodiments, the crystalline Form G includes a powder X-ray diffraction pattern with a characteristic peak represented by the angle 2-theta shown in the fourth pattern from the top of FIG.

Example 6
Discovery of Ponatinib Polymorphs Initial efforts to discover polymorphs of ponatinib were divided into two stages. The third stage included starting material characterization, feasibility testing, and solubility testing to provide data for selecting the solvent for the fourth stage. Phase 4 included 192 milliliter (ml) scale polymorphism screening experiments. From these initial efforts, 11 polymorphs of ponatinib free base have been identified: Forms A, B, C, D, E, F, G, H, I, J, and K. It's been found.

Step 1: Characterization of Starting Materials The synthesis described later herein yielded the compound ponatinib free base, which was characterized by amide coupling reaction of the amine and methyl ester subunits. Approximately 20 grams of free base (total of two batches designated F09-05575 and F09-05576) was obtained as a pale yellow solid. The starting material was characterized by XRPD, digital imaging, DSC, TGMS and HPLC.

Figure 84 shows the XRPD patterns of the free base starting material, the two patterns representing the two batches above (F09-05575: bottom pattern; and F09-05576: top pattern).

Figure 85 is a DSC curve of ponatinib free base starting material batch F09-05575 with endothermic events at T _peak = 182.6°C and T _peak = 199.0°C (major). The major endotherm corresponds to a melting event and appears to involve a desolvation process (observed in the TGA/SDTA trace of this batch).

Figure 86 is a DSC curve of ponatinib free base starting material batch F09-05576, showing an endothermic event at T _peak =199.6°C. The endotherm corresponds to a melting event and appears to involve a desolvation process (observed in the TGA/SDTA trace of this batch).

Figure 87 is a plot showing the TGA and SDTA thermograms of ponatinib free base starting material batch F09-05575.

Figure 88 is a plot showing the TGA and SDTA thermograms of ponatinib free base starting material batch F09-05576.

TGA and TGMS analyzes showed that batch F09-05575 had only one stage of mass loss (0.9% in the temperature range 25-210°C), whereas batch F09-05576 had two stages of mass loss. was observed (0.3% mass loss in the temperature range 25-120°C and 0.9% mass loss in the temperature range 120-210°C). The mass loss observed in both batches corresponds to 2-methyltetrahydrofuran (confirmed by the m/z ratio observed in the MS data). The presence of this solvent in the residual amount is believed to originate from the last synthetic step of the ponatinib free base compound.

Experiments were performed to determine the purity of ponatinib free base compound using HPLC. HPLC revealed a purity of 99.5166% (area percent) for batch F09-05575 and a purity of 99.6869% (area percent) for batch F09-05576.

In various embodiments, alternative methods of preparing Form A resulted in samples of varying degrees of crystallinity.

Alternative Preparation Method for Form A Ponatinib Free Base Preparation 1
An M010578 sample of ABL411057 (2-Me-THF, 1.1 eq. aniline, 1.6 eq. KOtBu) in an amount of 180 g was crystallized from neat 1-propanol and the 1-PrOH wet product was then crystallized from neat 1-propanol. Trituration in diluted acetonitrile gave Form A with a purity of 99.39a%.

Preparation 2
A 180 g amount of ABL411060 (2-Me-THF, 26° C. IT, 1.1 eq. aniline, 1.6 Two samples of equivalent amounts of KOtBu) were obtained. The 1-PrOH solution was divided 9:1.

779.5 g (portion 9) of the 1-PrOH solution of M010578 above was crystallized overnight at ambient temperature. After filtration, the wet filter mass was triturated in 160 g of acetonitrile at 40° C., filtered and dried (50° C., 3 mbar) to yield 211.6 g (99.87 a%) of Form A ponatinib free base.

260 g of acetonitrile was added to 86.6 g (corresponding to 1) of the above 1-PrOH solution of M010578. After 1 hour, the suspension was filtered and the filter cake was washed with ACN/1-PrOH (3:1 v/v) and dried to yield 25.6 g (99.27 a%) of the free base. Crystallization and isolation from 1-propanol followed by trituration in acetonitrile gave a product with higher HPLC purity than isolation by precipitation from an ACN/1-PrOH mixture.

Stage 1: Solubility Testing Quantitative solubility testing of ponatinib free base starting material was performed using a set of 20 solvents. After preparing a slurry with an equilibration time of 24 hours, the slurry was filtered. Solubility was determined from saturated solutions by HPLC. The residual solids were characterized by XRPD. The results are summarized in Table 25 below.

The material obtained from 19 out of 22 different solubility evaluations was the same polymorph as the starting material free base, designated Form A. The solid obtained from the slurry with cyclohexanone showed a different XRPD and was designated as B class form. Form B was further characterized as four solvates as described above.

Feasibility Study of Ponatinib Free Base Compound A feasibility study was conducted to attempt to obtain an amorphous free base material that could be used in several stage 4 crystallization techniques. Two techniques were used: milling and freeze drying. The results are shown below.

Grinding Two grinding experiments were conducted at a frequency of 30 Hz and two different durations, as summarized in Table 26 below. After crushing for 60 or 120 minutes, the material remained crystalline (Form A).

Lyophilization Eight lyophilization experiments were performed on ponatinib free base compound. These experiments are summarized in Table 27 below.

Amorphous materials were obtained with solvates such as 2,2,2-trifluoroethanol (TFE) and TFE/water mixtures. In experiments performed with 2-methyltetrahydrofuran, DMA/water (90:10) and THF, three new crystal forms were observed and designated as B class, D and E class. In the fourth stage of screening, B class and E class forms were also observed, and the results suggested that these were isomorphic structures. The remaining experiments performed with methanol and dichloromethane produced two types of less crystalline materials (Form C hypocrystalline and Form I hypocrystalline, respectively).

This new crystalline form was further analyzed and characterized by DSC, TGMS and HPLC. Forms D and E were confirmed to be solvates (1:1 API/DMA and 1:1 API/THF, respectively).

The low-crystalline material obtained from methanol (C low-crystalline) and the low-crystalline material obtained from dichloromethane (I low-crystalline) had a small amount of residual solvent (in the temperature range 40 °C to 150 °C, respectively). 1.3% and 0.5% in the interval 40°C to 175°C).

Freeze-drying with methanol was not optimal for producing a low-crystalline material and was therefore used to produce this material for use in the fourth step of cooling/evaporation crystallization and vapor diffusion onto solids experiments. A method using dichloromethane was chosen.

Based on the feasibility testing and dissolution behavior results of ponatinib free base, the solvent for the fourth stage of the experiment was selected.

Solvent Evaluation Quantitative solubility testing was performed on free base starting material batch F09-05575 to select the screening solvent and determine the concentration range to be used in the screen. A set of 20 solvents was used for this screening. For each solvent, a standard 1.8 ml screw cap vial contained 40 mg of starting material, 200 μl of solvent, and a magnetic stir bar. The vial was then capped and equilibrated for 24 hours at 25° C. with stirring. The resulting mixture (slurry) was filtered (0.5 micron) and the separated mother liquor was diluted into two dilutions selected according to the calibration curve. The amount of API in the diluted solution was determined by HPLC analysis (DAD). Calibration curves were obtained from stock solutions of two free base compounds prepared separately in 2,2,2-trifluoroethanol.

After solubility was determined, residual solvent was evaporated from each vial (slurry) under vacuum at ambient temperature. All of the obtained residues were analyzed by powder X-ray diffraction for new crystal forms.

Feasibility Testing Experimental conditions for feasibility testing of free base compounds are summarized in Table 28 below. After the experiment, HPLC analysis was performed to determine the purity and thermal analysis was performed to determine the thermal behavior of each form.

Experimental Design and Protocol for Polymorphic Screening A polymorphic screening experiment for the ponatinib free base compound was conducted on the milliliter (ml) scale using 192 different conditions, and six different crystallization methods were used in this experiment: : cooling - evaporation, addition of anti-solvent, grinding, slurry, vapor diffusion into solution and vapor diffusion onto solid.

Cooling-Evaporation Crystallization Experiments Twenty-four ml-scale cooling-evaporation experiments were performed in 8 ml vials using 24 different solvents and one concentration. Liquid (dichloromethane) was added to 25 mg of ponatinib free base in each vial. The sample was freeze-dried to obtain a powdered, low-crystalline material. Screening solvent was then added until a concentration of approximately 60 mg/ml was reached (see Table 29 below). The vial was capped and subjected to the temperature profile described in Table 30 below. The mixture was cooled to 5° C. and held at that temperature for 48 hours before the vial was placed under vacuum. Solvents were evaporated at 200 mbar or 10 mbar for several days and analyzed by XRPD and digital imaging.

Rapid Crystallization by Addition of Poor Solvent For rapid crystallization experiments, 23 different solvents and 18 different anti-solvents were used and 48 different crystallization conditions were used (see Table 31 below). . For each solvent, a stock solution was prepared and filtered into a set of 8 ml vials after 17 hours of equilibration to reach the concentration of ponatinib free base in each case at saturation at ambient temperature. A different antisolvent was added to each of these vials using a solvent to antisolvent ratio of 1:0.25. If no precipitation occurred, this ratio was increased to 1:4 with a 60 minute wait between additions. The solids that precipitated during the waiting period between antisolvent additions were separated by centrifugation. If no solid was obtained, the solvent was completely evaporated under vacuum at room temperature. If a solid was obtained, it was analyzed by XRPD and digital imaging.

Milling Experiments In the droplet milling method, a small amount of solvent is added to the ponatinib free base raw material and it is milled in a stainless steel milling jar containing two stainless steel milling balls. In this way, the effects of 24 different solvents (see Table 32) were investigated. Typically, 30 mg of starting material was ground and analyzed.

Slurry Experiments A total of 48 slurry experiments were conducted using ponatinib free base and 24 different solvents at 10°C and 30°C for 2 weeks each. Table 33 below summarizes the experimental conditions. Experiments were carried out by stirring a suspension of substances in a solvent at a controlled temperature. At the end of the slurry time, the vial was centrifuged to separate the solids and mother liquor. The solid was further dried under full vacuum at room temperature and analyzed by XRPD and digital imaging.

Vapor Diffusion into Solution In vapor diffusion experiments, a saturated solution of ponatinib free base was exposed to solvent vapor for two weeks at room temperature. A volume of the saturated solution was transferred to an 8 ml vial with the lid open, and 2 ml of the antisolvent was placed in a 40 ml vial with the lid closed (see Table 34 below). After two weeks, solid formation of the sample was confirmed. If solids were present, the liquid was separated from the solids. After the samples were dried under vacuum (200 mbar or 10 mbar), they were analyzed by XRPD and digital imaging.

Vapor Diffusion onto Solids In this vapor diffusion experiment, amorphous ponatinib free base was exposed to solvent vapor for two weeks at room temperature. The API was added as a liquid to an 8 ml vial and then lyophilized. The 8 ml vial containing the amorphous material was left open and placed in a 40 ml vial containing 2 ml of antisolvent and closed (see Table 35 below). After two weeks, the solids were analyzed by XRPD and digital imaging. If the solid was liquefied by vapor, the sample was dried under vacuum (200 mbar or 10 mbar) and then analyzed by XRPD and digital imaging.

Physical Stability and Scale-up of Selected Ponatinib Polymorphs The purpose of this study was to reproduce and further characterize the solid state forms of ponatinib identified in the studies described hereinabove. This study revealed that Form D (isomorphic solvate) and Form F (monohydrate) are physically stable under ambient conditions for at least 10 months. The B class and E class forms as well as Forms G, H, I (low crystallinity) and J (low crystallinity) converted to Form A during a period of 10 months under ambient conditions.

Scale-up of Form H and Form J (low crystallinity) was successful. Attempts to scale up Type G resulted in Type A. The scale-up project was implemented in three stages:
First step: storing the various forms obtained in the previous studies for 8-10 months under ambient conditions and then examining their physical stability by XRPD;
Step 2: Scale up the selected solid form of ponatinib free base to 50-120 mg for further characterization; and Step 3: Solvate state, thermal properties and Reveal physical stability.

Results of the first stage Form D (isomorphic solvate) and Form F (monohydrate) are stable during the test period. Both the Form B and E class isomorphic solvates converted to Form A. Form G, Form H, Form I (low crystallinity) and Form J (low crystallinity) were all converted to Form A. Figure 89 tabulates the physical stability of several solid state forms of ponatinib.

Stage 2: Scale-up of selected free base forms of ponatinib Forms G, H and J (low crystallinity) were selected for scale-up studies. The experimental conditions for scale-up were adapted from those of the polymorphism screen disclosed herein. Scale-up was successful in H-form and J-form (low crystallinity). Figure 90 tabulates the results of scale-up experiments for selected free base forms.

Third stage: Characterization of the form obtained in scale-up The solid form scaled up in the previous stage and shape-confirmed by XRPD was further characterized by DSC, TGMS, FTIR, HPLC and DVS. Form A, which resulted from an attempt to scale up Form G, was not further characterized. Furthermore, the physical stability against accelerated aging conditions (40° C., 75% RH for 1 week) was investigated. FIG. 91 tabulates various characterizations of ponatinib free base forms that were successfully reproduced on the 120 mg scale.

Pharmaceutical Compositions and Treatment of Physiological Conditions Therewith The present disclosure provides a therapeutically effective amount of a crystalline form of ponatinib hydrochloride disclosed herein and at least one pharmaceutically acceptable carrier, excipient, or excipient. A pharmaceutical composition comprising: In certain embodiments, the unit dosage form of the pharmaceutical composition comprises a single crystalline form of ponatinib hydrochloride as the API. Alternatively, the unit dosage form of the pharmaceutical composition comprises two or more crystalline forms of ponatinib hydrochloride. In certain embodiments, more than about 50%, more than about 70%, more than about 80%, or more than about 90% of the single crystalline forms present in the composition are of one of the selected forms. It is. In any of the above embodiments, one or all crystalline forms are substantially pure. For example, in certain embodiments, the pharmaceutical composition comprises substantially pure ponatinib hydrochloride Form A and at least one pharmaceutically acceptable carrier, excipient or excipient. Alternatively, the pharmaceutical composition comprises Forms A and J of ponatinib hydrochloride and at least one pharmaceutically acceptable carrier, excipient or excipient. Other variations on this subject matter will be readily apparent to those skilled in the art having the benefit of this disclosure.

The at least one pharmaceutically acceptable carrier, diluent, excipient or excipient can be readily selected by one of skill in the art and will be determined by the desired method of administration. Examples of suitable methods of administration include oral, nasal, parenteral, topical, transdermal, and rectal administration. The pharmaceutical compositions disclosed herein may take any pharmaceutical form recognized as appropriate by those skilled in the art. Suitable pharmaceutical forms include solid, semisolid, liquid or lyophilized formulations such as tablets, powders, capsules, suppositories, suspensions, liposomes and aerosols.

Various solid forms of ponatinib and various solid forms of ponatinib hydrochloride may be administered to a subject in need of treatment, alone or in any combination, in therapeutically effective amounts. Similarly, any of the solid forms of ponatinib and ponatinib hydrochloride disclosed herein, alone or in any combination, can subsequently be used to treat various disease states in animals, including humans. Can be formulated into pharmaceutical compositions. For example, a pharmaceutical composition comprising any single or combination of ponatinib and/or polymorphs of ponatinib hydrochloride is administered to a subject in need thereof by administering a therapeutically effective amount of the pharmaceutical composition to a subject in need thereof. can be used to treat CML or Ph+ALL.

III. Synthesis of Ponatinib and Ponatinib Hydrochloride Ponatinib free base and Ponatinib HCl are the products of a four-step convergent synthesis illustrated in Scheme 1. In step 1, the "methyl ester" intermediate AP25047 is synthesized from starting materials AP24595, AP28141 and AP25570. In step 2, the "aniline" intermediate AP24592 is synthesized from the starting material AP29089. Step 3 is a base-catalyzed coupling of AP25047 and AP24592 to produce ponatinib free base, also called AP24534, which is isolated as free base. Step 4 is the formation and crystallization of ponatinib monohydrochloride in ethanol.

A representative synthetic route for ponatinib HCl is referred to as Step C.

Scheme 1 : Process C

Step 1: Synthetic Overview and Synthetic Scheme for the AP25047 (“Methyl Ester”) Intermediate Step 1 of the ponatinib HCl process consists of three reaction sequences (1a, Synthesis of the methyl ester intermediate AP25047 (referred to as 1b and 1c) is performed without intermediate isolation ("shortened"). Two juxtaposed aromatic ring systems connected by a single alkyne linker are constructed by two tandem palladium/copper catalyzed Sonogashira couplings and an in situ desilylation reaction under basic conditions. The crude AP25047 product is then subjected to a series of processing steps designed to remove residual inorganic catalyst and treat by-products. These operations include crystallization of AP25047 as the HCl salt from the non-polar solvent toluene (unit operation 1.3), aqueous work-up and filtration through a silica gel plug (unit operation 1.4) and the polar solvent 2-propanol. Includes crystallization from (unit operation 1.5). These two crystallizations constitute orthogonal purification to eliminate impurities of related substances with different polarities. Crystallization of the HCl salt from toluene and solvent washing is controlled by in-process analytical testing for specific process impurities. The final crystallization of the AP25047 intermediate from 2-propanol has been subjected to multivariate DoE studies to define a design space that ensures the exclusion of other impurities resulting from the abbreviated reaction. A series of eight in-process tests in Stage 1 provides quantitative analytical control of reaction completion, exclusion of impurities, and effective removal of residual solvent.

Scheme 2 : Step 1 - Synthesis of AP25047

Unit operation 1.1: First Sonogashira reaction A reactor is charged with AP24595, palladium tetrakistriphenylphosphine (Pd(PPh ₃ ) ₄ ), copper(I) iodide (Cul), triethylamine, and tetrahydrofuran (THF). After the mixture is stirred and degassed with nitrogen, the previously degassed AP28141 is charged. The resulting mixture is brought to 45-55°C and maintained for at least 3 hours. The completion of the reaction is determined by IPC-1 (HPLC). If IPC-1 criteria are met, the mixture is concentrated to the desired volume and cooled.

Unit operation 1.2: Deprotection/Second Sonogashira reaction AP25570, another palladium tetrakis triphenylphosphine (Pd(PPh ₃ ) ₄ ), copper(I) iodide (Cul) and tetrahydrofuran (THF) were added to the reactor. ). The mixture is concentrated and the water content determined by IPC-2 (KF). If IPC-2 criteria are met, warm the mixture to 45-60°C and slowly add 25% sodium methoxide in methanol. The reaction mixture is stirred and held at 45-55° C. for 30-60 minutes. The progress of the reaction is determined by IPC-3 (HPLC). The reaction mixture may be maintained at a temperature below the above temperature during IPC analysis. If IPC-3 criteria are met, continue the process to unit operation 1.3.

Unit Operation 1.3: Isolation of AP25047.HCl While stirring the cold reaction mixture, the reaction is stopped by the addition of hydrogen chloride gas. Once a precipitate has formed, remove residual hydrogen chloride from the suspension by nitrogen purge. Tetrahydrofuran (THF) is replaced with toluene by azeotropic distillation under reduced pressure. The resulting warm slurry is filtered using an agitating filter dryer, and the filtered mass is washed by trituration with toluene. The content of the process impurity AP29116 is determined by IPC-4 (HPLC). If IPC-4 criteria are met, the wet filter mass is stirred and dried at 35-45° C. (jacket temperature) under nitrogen flow and vacuum. Monitor drying by IPC-5 (LOD, gravimetry). Once IPC-5 standards are met, the crude AP25047 HCl is removed and packed into FEP bags inside plastic containers. Isolated AP25047 HCl can be stored for up to 7 days before further processing.

Unit Operation 1.4: Work-up The crude AP25047 HCl solid is placed in a vessel with dichloromethane (DCM) and washed with aqueous ammonia. In order to restore the yield, the aqueous phase is back-extracted with DCM and the combined organic phases are washed a second time with aqueous ammonia. The organic layer is then washed with aqueous hydrochloric acid until the aqueous phase reaches a pH of 1-2 as indicated by IPC-6 (pH test paper). If the IPC-6 criteria are met, the organic phase is treated with aqueous sodium bicarbonate until the aqueous wash reaches a pH of NLT7 as indicated by IPC-7 (pH paper). After briefly concentrating the organic phase, fresh dichloromethane is added. After the organic solution is passed through a pad of silica gel, it is washed again with fresh dichloromethane to increase product recovery.

Unit Operation 1.5: Crystallization of AP25047 The dichloromethane solution is concentrated under reduced pressure and the dichloromethane is replaced by 2-propanol by azeotropic distillation under reduced pressure to the desired final volume range. The resulting suspension is then cooled, stirred and further aged.

Unit operation 1.6: Isolation/Drying The precipitated product is isolated in a stirred filter dryer under a stream of nitrogen and the filter mass is washed with 2-propanol. The wet filter mass is stirred and dried under nitrogen flow and vacuum at 45-55° C. (jacket temperature). Monitor drying by IPC-8 (LOD, gravimetry). If IPC-8 standards are met, the product is collected and packaged in polyethylene bags, heat-sealed mylar-coated aluminum foil bags, and placed in HDPE shipping containers (expected yield range is 65 ~89%).

Step 2: Synthesis Overview and Synthetic Scheme for AP24592 (“Aniline”) Intermediate Step 2 of the ponatinib HCl process is the synthesis of aniline intermediate AP24592 by catalytic hydrogenation of the nitro-aromatic starting material AP29089, illustrated below. be. The reaction is carried out in ethyl acetate, a solvent in which the starting materials and products are highly soluble. The catalyst for this reaction is palladium on carbon, and hydrogen is introduced as a gas directly into the reaction mixture. At the end of the reaction, exchanging the solvent from ethyl acetate to n-heptane by distillation promotes spontaneous crystallization of AP24592 and yields highly pure material. This crystallization has been shown to be highly effective in purification, as most of the process impurities remain solubilized in n-heptane.

Three in-process controls for step 2 were HPLC of the reaction mixture to confirm starting material consumption, GC measurement of ethyl acetate after azeotropic solvent exchange to n-heptane, and gravimetric measurement of solvent loss on drying. be.

Scheme 3 : Step 1 to Step 2: Synthesis of AP24592

Unit Operation 2.1: Dissolution and Hydrogen Purging AP29089, 10% palladium on carbon and ethyl acetate are charged into the reactor and the suspension is stirred under hydrogen pressure.

Unit Operation 2.2: Hydrogenation After pressurizing the reactor with hydrogen until a stable pressure range is reached, the mixture is stirred under an atmosphere of hydrogen for at least a further 4 hours. The reactor is depressurized and a sample is taken to assess completion of the reaction (IPC-1). If IPC-1 criteria are met, continue the process to unit operation 2.3.

Unit Operation 2.3: Concentration/Crystallization Pass the reaction mixture through a filter cartridge to remove the catalyst and wash the cartridge with fresh ethyl acetate. The combined filtrate and wash solution are concentrated under vacuum to remove the desired volume of ethyl acetate. Add n-heptane and continue distillation under vacuum to target volume. Measure the ethyl acetate content by IPC-2 (GC). If the criteria of lPC-2 are met, continue the process to unit operation 2.4.

Unit Operation 2.4: Isolation/Drying The solid product is dried under vacuum at the target temperature range. The completion of drying is determined by IPC-3 (LOD, weight measurement). AP24592 is obtained as a white to yellow solid in the range of 80-97% (based on AP29089 input).

Step 3: Synthetic Overview and Synthetic Scheme of Ponatinib Free Base Step 3 is the synthesis of ponatinib free base by base-catalyzed reaction of AP25047 and AP24592, as shown in Scheme 4. This reaction is carried out in the presence of the strong base potassium tert-butoxide under substantially anhydrous conditions to minimize undesired hydrolysis of the methyl ester of AP25047 to the corresponding unreactive carboxylic acid. The presence of this by-product not only reduces the yield but also complicates downstream processing in the work-up of the reaction. In the drying of the reaction mixture by a series of azeotropic distillations, in-process water testing and control ensures reliable reaction and quantitative consumption of the starting materials. Reaction conditions and crystallization parameters that ensure the exclusion of process impurities are well understood in light of DoE testing.

Scheme 4 : Step 3 - Synthesis of AP24534 free base

Unit Operation 3.1: Drying the Reaction Mixture AP25047, AP24592 and 2-methyltetrahydrofuran (2-Me-THF) are charged to a reactor. The mixture is concentrated under reduced pressure to the target volume. Add new 2-methyltetrahydrofuran and carry out the distillation again. After adding 2-methyltetrahydrofuran once again and carrying out a distillation cycle, the water content of the mixture is determined by IPC-1 (KF). If IPC-1 criteria are met, continue the process to unit operation 3.2.

Unit Operation 3.2: Reaction Potassium tert-butoxide (KOtBu) is added while stirring and maintaining the suspension at a target temperature in the range 13-23°C. After 3 hours or more have elapsed, the progress of the reaction is determined by HPLC (IPC-2). If the IPC criteria are met, continue the process to unit operation 3.3.

Unit Operation 3.3: Termination and Extraction The reaction mixture is diluted with 2-methyltetrahydrofuran (2-Me-THF) and the reaction is quenched by addition of aqueous sodium chloride solution. Separate the organic layer and extract the aqueous layer twice with 2-methyltetrahydrofuran. The combined organic layers are washed successively with aqueous sodium chloride solution and water. The organic layer is then aged at 15-30°C.

Unit Operation 3.4: Concentration/Solvent Exchange After ripening (see unit operation 3.3), the mixture is passed through a cartridge filter and concentrated under vacuum to the target volume. Add 1-propanol and stir at high temperature to form a solution, distill under vacuum to a target volume, and then gradually cool to a temperature range of 20-30°C.

Unit Operation 3.5: Crystallization A solution of the product in 1-propanol is aged with stirring at a temperature of 20-30° C. until the presence of solids is visually observed. Acetonitrile is added to the suspension while stirring and the resulting suspension is further aged for 60-120 minutes at 20-30° C. before isolation in the next unit operation.

Unit Operation 3.6: Isolation/Drying The slurry produced in Unit Operation 3.5 is isolated in a filter/dryer under vacuum. Wash the solid twice with a mixture of 1-propanol and acetonitrile. The solid is then dried under vacuum and monitored by IPC-3 (LOD, gravimetrically). If IPC criteria are met, the product is removed as an off-white to yellow solid and stored in double polyethylene bags at ambient temperature.

Step 4: Synthesis Overview and Synthetic Scheme of Ponatinib HCl Step 4 of the ponatinib HCl process consists of the combination of equimolar amounts of ponatinib free base and hydrochloric acid in ethanol to form the monohydrochloride salt and the induction of crystallization by seeding. It is. The parameters of this process have been investigated in DoE studies to produce the desired solid form and the effect of this process on particle size distribution. The synthesis scheme for step 4 is shown in scheme 5.

Scheme 5 : Step 4 - Synthesis of ponatinib HCl

Unit Operation 4.1: Dissolution AP24534 free base and absolute ethanol (EtOH) are placed in a reactor and stirred into solution at 60-75°C. Confirm dissolution by visual observation.

Unit operation 4.2: Clarification After the solution is passed through a filter, it is washed with ethanol at 60-78°C.

Unit Operation 4.3: Acidification/Seeding Concentrate the product solution under vacuum to the target volume. While stirring, add the first portion (approximately 25%) of a 1N ethanolic solution of hydrogen chloride to the reactor. Crystallization is initiated by seeding the solution with qualified AP24534HCl at a temperature of 60-70°C. Continue the process until unit operation 4.4.

Unit Operation 4.4: Crystallization Once visual observation confirms the presence of solids in the reactor, slowly add the remainder of the 1N ethanolic solution of hydrogen chloride (approximately 75%) to the stirring mixture. The mixture is aged for at least 10 minutes and IPC-1 is performed to measure the pH of the solution. If the IPC criteria are met, the mixture is cooled to a temperature of 5-15° C. and aged with stirring.

Unit Operation 4.5: Isolation/Drying Isolate the solid product by filtration and wash with ethanol at a temperature of 5-15°C. Remove excess ethanol from the solids by gentle stirring and nitrogen flow at ambient temperature. The solid is then dried under vacuum at 60-70°C. Monitor drying by IPC-2 (LOD, gravimetry). Once IPC-2 criteria are met, ponatinib HCl is removed as an off-white to yellow solid, packaged in double polyethylene bags and stored in plastic drums at 20-30°C.

It is to be understood that the foregoing description is illustrative and explanatory in nature and is intended to explain the general inventive concept of the present disclosure and its preferred embodiments. Those skilled in the art having the benefit of this disclosure will recognize, through routine experimentation, obvious modifications and variations without departing from the spirit and scope of this disclosure. Accordingly, the present disclosure is not limited to the above description, but rather by the following claims and their equivalents.

Claims (4)

3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl} Polymorphic crystals of benzamide monohydrochloride. A pharmaceutical composition comprising the polymorphic crystal according to claim 1 and a pharmaceutically acceptable carrier or excipient. A therapeutic agent for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), comprising a therapeutically effective amount of the polymorphic crystal according to claim 1 or the pharmaceutical composition according to claim 2. Therapeutic agents, including substances. Use of the polymorphic crystal according to claim 1 for the treatment of chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL).

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